一氧化氮与吗啡镇痛作用及其镇痛耐受关系的实验研究
|
摘要
一氧化氮与吗啡镇痛作用及其镇痛耐受关系的实验研究
吗啡是目前最常用于严重疼痛和慢性疼痛治疗的阿片类药物，其主要缺点是容易出现镇痛耐受，从而降低长期应用的镇痛效果。近年来，针对吗啡镇痛耐受已经开展了许多研究，通常认为其发生机制非常复杂，涉及许多生物因子和神经传导通路，并且其中的许多因素和环节尚未被完全阐明。一氧化氮(NO)是近年来倍受生物医学界关注的一种气体分子，作为一种重要的化学递质和细胞内信号分子，NO在机体内的许多生物调节机制中发挥着关键性作用。目前已有一些研究试图阐释NO在伤害性感受中的作用以及NO与阿片受体的相互作用，尤其是NO对吗啡镇痛及其镇痛耐受的影响，但是由于各研究所采用的实验动物模型、观察方法、给药途径和用药方法等方面的差别，因此未能取得一致的结果。由鉴于此，本研究采用福尔马林炎性疼痛和热甩尾测痛两种大鼠模型观察了单次和长期全身应用非特异性NOS抑制剂—L-NAME对吗啡镇痛作用及其镇痛耐受的影响；研究中检测了脊髓和中脑的c-fos基因表达、细胞外谷氨酸含量以及nNOSmRNA、NR1A(NMDA receptor subunit-1A)mRNA和NR2A(NMDA receptor subunit-2A)mRNA表达的变化，以探讨NO与吗啡镇痛及其镇痛耐受机制之间的关系。本研究的主要目的是进一步阐释NO在吗啡镇痛及其镇痛耐受中的作用，以为临床上解决吗啡镇痛耐受这一难题提供有益的启示。
第一部分 单次应用L-NAME对吗啡镇痛作用的影响
选择健康成年Sprague-Dawley(SD)大鼠60只，将其随机分成6组：1组(n=12)为对照组：腹腔注射生理盐水1ml，30min后再次腹腔注射生理盐水1ml；2组(n=6)：腹腔注射生理盐水1ml，30min后腹腔注射L-NAME 10mg／kg；3组(n=12)：腹腔注射生理盐水1ml，30min后腹腔注射L-NAME 20mg／kg：4组(n=12)：腹腔注射生理盐水1ml，30min后腹腔注射吗啡10mg／kg；5组(n=6)：腹腔注射L-NAME 10mg／kg，30min后腹腔注射吗啡10mg／kg。6组(n=12)：腹腔注射L-NAME 20mg／kg，30min后腹腔注射吗啡10mg／kg。在各组末次给药30min后，于大鼠左后掌皮下注射5％福尔马林0.1ml，随后50min内记录其舔咬注射足时间。除2组和5组之外，其他组动物分为两个亚组，第一亚组动物记录完毕后取L_5脊髓节段和中脑标本做c-fos免疫组织化学检查。第
Morphine is an opioid most frequently used for management of severe and chronic pain. The main disadvantage of morphine is the development of tolerance to analgesia which decreases its long-term effect of pain relief. A number of studies on tolerance to morphine analgesia have been done for the past few years. It is generally belived that the mechanisms underlying tolerance to morphine analgesia are highly complicated and involve many biological molecules and neuronal pathways, some of which still remain unclear. Nitric oxide (NO), a gaseous molecule, has increasingly become the interests of the biomedical researches. As an important chemical mediator and intracellular signaling molecule, NO plays a key modulatory role in numerous biological mechanisms. There have been several relevant studies attempting to clarify the interaction of NO and opioid receptors and the roles of NO in the nociceptive processes and, particularly in the actions of NO on morphine analgesia and tolerance, however, the no consistent results are achieved due to the differences in the experimental animal models, study methods and drug regimens. Accordingly, we carried out the present experiments, using both the formalin-induced inflammation and the thermal tail-flick rat models, to explore the effects of a single or chronic systemic administration of nitric oxide synthase inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) on morphine analgesia and tolerance by measuring the expressions of c-fos gene, nNOSmRNA, NRlAmRNA, NR2AmRNA, and the extracellular concentrations of glutamate in spinal cord and midbrain, therey indentifing the relationship between NO and the mechanisms related to morphine analgesia and tolerance. The main purpose of our study is to further evaluate actions of NO on morphine analgesia and tolerance so as to provide a favorable inspiration for clinically dealing with tolerance to morphine analgesia.
吗啡是目前最常用于严重疼痛和慢性疼痛治疗的阿片类药物，其主要缺点是容易出现镇痛耐受，从而降低长期应用的镇痛效果。近年来，针对吗啡镇痛耐受已经开展了许多研究，通常认为其发生机制非常复杂，涉及许多生物因子和神经传导通路，并且其中的许多因素和环节尚未被完全阐明。一氧化氮(NO)是近年来倍受生物医学界关注的一种气体分子，作为一种重要的化学递质和细胞内信号分子，NO在机体内的许多生物调节机制中发挥着关键性作用。目前已有一些研究试图阐释NO在伤害性感受中的作用以及NO与阿片受体的相互作用，尤其是NO对吗啡镇痛及其镇痛耐受的影响，但是由于各研究所采用的实验动物模型、观察方法、给药途径和用药方法等方面的差别，因此未能取得一致的结果。由鉴于此，本研究采用福尔马林炎性疼痛和热甩尾测痛两种大鼠模型观察了单次和长期全身应用非特异性NOS抑制剂—L-NAME对吗啡镇痛作用及其镇痛耐受的影响；研究中检测了脊髓和中脑的c-fos基因表达、细胞外谷氨酸含量以及nNOSmRNA、NR1A(NMDA receptor subunit-1A)mRNA和NR2A(NMDA receptor subunit-2A)mRNA表达的变化，以探讨NO与吗啡镇痛及其镇痛耐受机制之间的关系。本研究的主要目的是进一步阐释NO在吗啡镇痛及其镇痛耐受中的作用，以为临床上解决吗啡镇痛耐受这一难题提供有益的启示。
第一部分 单次应用L-NAME对吗啡镇痛作用的影响
选择健康成年Sprague-Dawley(SD)大鼠60只，将其随机分成6组：1组(n=12)为对照组：腹腔注射生理盐水1ml，30min后再次腹腔注射生理盐水1ml；2组(n=6)：腹腔注射生理盐水1ml，30min后腹腔注射L-NAME 10mg／kg；3组(n=12)：腹腔注射生理盐水1ml，30min后腹腔注射L-NAME 20mg／kg：4组(n=12)：腹腔注射生理盐水1ml，30min后腹腔注射吗啡10mg／kg；5组(n=6)：腹腔注射L-NAME 10mg／kg，30min后腹腔注射吗啡10mg／kg。6组(n=12)：腹腔注射L-NAME 20mg／kg，30min后腹腔注射吗啡10mg／kg。在各组末次给药30min后，于大鼠左后掌皮下注射5％福尔马林0.1ml，随后50min内记录其舔咬注射足时间。除2组和5组之外，其他组动物分为两个亚组，第一亚组动物记录完毕后取L_5脊髓节段和中脑标本做c-fos免疫组织化学检查。第
Morphine is an opioid most frequently used for management of severe and chronic pain. The main disadvantage of morphine is the development of tolerance to analgesia which decreases its long-term effect of pain relief. A number of studies on tolerance to morphine analgesia have been done for the past few years. It is generally belived that the mechanisms underlying tolerance to morphine analgesia are highly complicated and involve many biological molecules and neuronal pathways, some of which still remain unclear. Nitric oxide (NO), a gaseous molecule, has increasingly become the interests of the biomedical researches. As an important chemical mediator and intracellular signaling molecule, NO plays a key modulatory role in numerous biological mechanisms. There have been several relevant studies attempting to clarify the interaction of NO and opioid receptors and the roles of NO in the nociceptive processes and, particularly in the actions of NO on morphine analgesia and tolerance, however, the no consistent results are achieved due to the differences in the experimental animal models, study methods and drug regimens. Accordingly, we carried out the present experiments, using both the formalin-induced inflammation and the thermal tail-flick rat models, to explore the effects of a single or chronic systemic administration of nitric oxide synthase inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) on morphine analgesia and tolerance by measuring the expressions of c-fos gene, nNOSmRNA, NRlAmRNA, NR2AmRNA, and the extracellular concentrations of glutamate in spinal cord and midbrain, therey indentifing the relationship between NO and the mechanisms related to morphine analgesia and tolerance. The main purpose of our study is to further evaluate actions of NO on morphine analgesia and tolerance so as to provide a favorable inspiration for clinically dealing with tolerance to morphine analgesia.
引文
1.Bredt DS, Snyder SH. Nitric oxide, a novel neuronal messenger. Neuron 1992;8 (1): 3-11.
2. Schuman EM, Madison DV. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 1991; 254 (5037): 1503-6.
3.Doursout MF, Liang Y, Chelly JE. NOS inhibitors exhibit antinociceptive properties in the rat formalin test. Can J Anaesth 2003; 50 (9): 909-16.
4.Yamaguchi H, Naito H. Antinociceptive synergistic interaction between morphine and n-omega nitro-L-arginine methyl ester on thermal nociceptive tests in the rats. Can J Anesth 1996; 43 (9): 975-81.
5. Przewlocki R, Machelska H, Przewlocka B. Inhibation of nitric oxide synthase enhances morphine antinociception in the rat spinal cord. Life Sci 1993;53 (1): PL1-5.
6. Majeed NH, Przewlocka B, Machelska H, Przewlocki R. Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice. Neuropharmacology 1994; 33 (2): 189-92.
7. Zek M, Uresin Y, Gungor M. Comparison of the effects of specific and nonspecific inhibition of nitric oxide synthase on morphine analgesia,tolerance and dependence in mice. Life Sci 2003; 72 (17): 1943-51.
8.Benamar K, Xin L, Geller EB, Adler MW. Modulation of morphine analgesia by a nitric oxide synthase inhibitor microinjected into the periaqueductal gray in rats. Analgesia 2002; 6 (1-3): 7-10.
9. Abacioglu N, Tunctan B, Akbulut E, Cakici I. Participation of the components of L-arginine/nitric oxide/cGMP cascade by chemically-induced abdominal constriction in the mouse. Life Sci 2000; 67 (10): 1127-37.
10. Pataki I, Telegdy G. Further evidence that nitric oxide modifies acute and chronic morphine actions in mice. Eur J Pharmacol 1998; 357 (2-3): 157-62.
11. Liang DY, Clark JD. Modulation of the NO/CO-cGMP signaling cascade during chronic morphine exposure in mice. Neurosci Lett 2004; 365 (1): 73-7.
12. Bhargava HN, Bian JT. N (G) -nitro-L-arginine reverses L-arginine induced changes in morphine antinociception and distribution of morphine in brain regions and spinal cord of the mouse. Brain Res 1997; 749 (2): 351-3.
13. Dunbar S, Yaksh TL. Effect of spinal infusion of L-NAME, a nitric oxide synthase inhibitor, on spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Neurosci Lett 1996; 207 (1): 33-6.
14.Harris JA. Using c-fos as a neural marker of pain. Brain Res Bull 1998;45 (1): 1-8.
15. Dubner R, Ruda MA. Activity-dependent neuronal plasticity following tissue injury and inflammation (Review) . Trends Neurosci 1992; 15 (3): 96-103.
16. Honor P, Buritova J, Besson JM. Carrageenin-evoked c-Fos expression in rat lumbar spinal cord: the effects of indomethacin. Eur J Pharmacol 1995;272 (2-3): 249-59.
17. Hunter JC, Woodburn VL, Durieux C, Pettersson EK, Poat JA, Hughes J. C-fos antisense oligodeoxynucleotide increases formalin-induced nociception and regulates preprodynorphin expression. Neurosci 1995; 65 (2): 485-92.
18. Garthwaite J, Garthwaite G, Palmer RM, Moncada S. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol 1989; 172 (4-5): 413-6.
19. Bredt DS, Snyder SH. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Nat 1 Acad Sci USA 1989; 86 (22): 9030-3.
20. East SJ, Garthwaite J. NMDA receptor activition in rat hippocampus induceds cyclic GMP formation through the L-arginine-nitric oxide pathway. Neurosci Lett 1991; 123 (1): 17-9.
21.Mayer ML, Westbrook GL. The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 1987; 28 (3): 197-276. Review.
22. Vetter G, Geisslinger G, Tegeder I. Release of glutamate, nitric oxide and prostaglandin E2 and metabolic activity in the spinal cord of rats following peripheral nociceptive stimulation. Pain 2001; 92 (1-2): 213-8.
23. Watanabe C, Okuda K, Sakurada C, Ando R, Sakurada T, Sakurada S. Evidence that nitric oxide-glutamate cascade modulates spinal antinociceptive effect of morphine: a behavioural and microdialysis study in rats. Brain Res 2003: 990 (1-2): 77-86.
24. Skilling SR, Smullin DH, Beitz AJ, Larson AA. Extracellular amino acid concentrations in the dorsal spinal cord of freely moving rats following veratridine and nociceptive stimulation. JNeurochem 1988; 51 (1): 127-32.
25. Machelska H, Ziolkowska B, Mika J, Przewlocka B, Przewlocki R. Chronic morphine increases biosynthesis of nitric oxide synthase in the rat spinal cord. Neuroreport 1997; 8 (12): 2743-7.
26. Cuellar B, Fernandez AP, Lizasoain I, Moro MA, Lorenzo P, Bentura ML, Rodrigo J, Leza JC. Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal. Psychopharmacology 2000; 148 (1): 66-73.
27. Wong CS, Hsu MM, Chou YY, Tao PL, Tung CS. Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord. Br J Anaesth 2000; 85 (4): 587-91.
28. Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977; 4 (2): 161-74.
29. Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. The formalin test: an evaluation of the method. Pain 1992; 51 (1): 5-17.
30. Rosland JH, Tjolsen A, Maehle B, Hole K. The formalin test in mice: effect of formalin concentration. Pain 1990; 42 (2): 235-42.
31. Sakurada C, Sugiyama A, Nakayama M, Yonezawa A, Sakurada S, Tan-No K, Kisara K, Sakurada T. Antinociceptive effect of spinally injected L-NAME on the acute nociceptive response induced by low concentrations of formalin. Neurochem Int 2001; 38 (5): 417-23.
32．李淑琴，李文斌，孙晓彩，李清军，陈晓玲，艾洁．MK-801抑制福尔马林实验引起的大鼠脊髓背角环氧合酶-2的表达．生理学报2004：56(1)：66-72．
33．徐叔云，卞如濂，陈修 主编．药理实验方法学 第三版．人民卫生出版社 884-5．34.Dickenson AH, Sullivan AF. Peripheral origins and central modulation of subcutaneous formalin-induced activity of rat dorsal horn neurones. Neurosci Lett 1987; 83 (1-2): 207-11.
35. Dickenson AH, Sullivan AF. Subcutaneous formal in-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain 1987; 30 (3): 349-60.
36. Puig S, Sorkin LS. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 1996; 64 (2):345-55.
37. Hunskaar S, Hole K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 1987; 30 (1): 103-14.
38. Okuda K, Sakurada C, Takahashi M, Yamada T, Sakurada T. Characterization of nociceptive responses and spinal releases of nitric oxide metabolites and glutamate evoked by different concentrations of formalin in rats. Pain 2001; 92 (1-2): 107-15.
39.Davidson EM, Coggeshall RE, Carlton SM. Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviors in the rat formalin test. Neuroreport 1997; 8 (4): 941-6.
40. Malmberg AB, Gilbert H, McCabe RT, Basbaum AI. Powerful antinociceptiveeffects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T. Pain 2003; 101 (1-2): 109-16.
41. Chapman V, Haley JE, Dickenson AH. Electrophysiologic analysis of preemptive effects of spinal opioids on N-methyl-D-aspartate receptor-mediated events. Anesthesiology 1994; 81 (6): 1429-35.
42.Sakurada T, Sugiyama A, Sakurada C, Tan-No K, Yonezawa A , Sakurada S,Kisara K. Effect of spinal nitric oxide inhibition on capsaicin-induced nociceptive response. Life sci. 1996; 59 (11) :921-30.
43.Abbott FV, Melzack R, Leber BF Morphine analgesia and tolerance in the tail-flick and formalin tests: dose-response relationships. Pharmacol Biochem Behav 1982; 17 (6): 1213-9.
44.Babey AM, Kolesnikov Y, Cheng J, Inturrisi CE, Trifilletti RR, Pasternak GW. Nitric oxide and opioid tolerance. Neuropharmacology 1994; 33 (11):1463-70.
45.Rauhala P , Idanpaan-Heikkila JJ , Tuominen RK , Mannisto PT.N-nitro-L-arginine attenuates development of tolerance to antinociceptive but not to hormonal effects of morphine. Eur J Pharmacol 1994; 259 (1):57-64.
46.Wang XM, Yan JQ, Zhang KM, Mokha SS. Role of opioid receptors (mu, delta 1, delta 2)in modulating responses of nociceptive neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in the rat. Brain Res 1996; 739 (1-2): 235-43.
47.Chapman V, Dickenson AH. The combination of NMDA antagonism and morphine produces profound antinociception in the rat dorsal horn. Brain Res 1992;28; 573 (2): 321-3.
48.Meller ST, Gebhart GF. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 1993; 52 (2): 127-36
49.Wang H, Nei H, Zhang RX, Qiao JT. Peripheral nitric oxide contributes to both formalin- and NMDA-induced activation of nociceptors : an immunocytochemical study in rats. J Neurosci Res 1999; 57 (6): 824-9.
50.Malmberg AB, Yaksh TL. Spinal nitric oxide synthesis inhibition blocks NMDA-induced themal hyperalgesia and produces antinociception in the formalin test in rats. Pain 1993; 54 (3): 291-300.
51.Dambisya YM, Lee TL. Effects L-NG-nitro arginine methyl ester (L-NAME), L-NG-monomethyl arginine (L-NMMA) and L-arginine on the antinociceptive effects of morphine in mice. Methods Find Exp Clin Pharmacol 1995; 17 (9):577-82.
52.Meller ST, Pechman PS, Gebhart GF, Maves TJ. Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neurosci 1992; 50 (1): 7-10.
53.Moore PK, Oluyomi A0, Babbedge RC, Wallace P, Hart SL. L-NG-nitro argininemethyl ester exhibits antinociceptive activity in the mouse. Br J Pharmacol 1991; 102 (1): 198-202.
54. Roche AK, Cook M, Wilcox GL, Kajander KC. A nitric oxide synthesis inhibitor (L-NAME) reduces licking behavior and Fos-labeling in the spinal cord of rats during formalin-induced inflammation. Pain 1996; 66 (2-3):331-41.
55. Pelligrino DA, Laurito CE, VadeBoncouer TR. Nitric oxide synthase inhibition modulates the ventilatory depressant and antinociceptive actions of fourth ventricular infusions of morphine in the awake dog. Anesthesiology 1996;85 (6): 1367-77.
56. Xu JY, Tseng LF. Nitric oxide/cyclic guanosine monophosphate system in the spinal cord differentially modulates intracerebroventricularly administered morphine- and beta-endorphin-induced antinociception in the mouse. J Pharmacol Exp Ther 1995; 274 (1): 8-16.
57. Li XQ, Clark JD. Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. Brain Res Mol Brain Res 2001; 95 (1-2).- 96-102.
58.Tao YX, Johns RA. Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw. Neurosci 2002; 112 (2): 439-46.
59. Knowles RG, Palacios M, Palmer RM, Moncada S. Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase, Proc Natl Acad Sci USA 1989;86 (13): 5159-62.
60. Kolesnikov YA, Pick CG, Pasternak GW. NG-nitro-L-arginine prevents morphine tolerance. Eur J Pharmacol 1992; 221 (2-3): 399-400.
61.Dunbar SA, Pulai IJ. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat. J Pharmacol Exp Ther 1998; 284 (2): 678-86.
62. RohdeDS, DetweilerDJ, Basbaum AI. Formalin-evoked Fos expression in spinal cord is enhanced in morphine-tolerant rats. Brain Res 1997; 766 (1-2):93-100.
63. Sorkin LS. NMDA evokes an L-NAME sensitive spinal release of glutamate and citrulline. Neuroreport 1993; 4 (5): 479-82.
64.Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994; 14 (4): 2301-12.
65.Kitto KF, Haley JE, Wilcox GL.Involvement of nitric oxide in spinally mediated hyperalgesia in the mouse. Neurosci Lett 1992; 148 (1-2): 1-5.
66. MellerST, Dykstra C, Gebhart GF. Production of endogenous nitric oxide and activation of soluble guanylate cyclase are required for N-methyl-D-aspartate-produced facilitation of the nociceptive tail-flick reflex. Eur J Pharmacol 1992; 214 (1):93-6.
67.Dambisya YM, Lee TL. Role of nitric oxide in the induction and expression of morphine tolerance and dependence in mice. Br J Pharmacol 1996; 117(5): 914-8.
68. Herman BH, Vocci F, Bridge P. The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal.Medication development issues for opiate addiction. Neuropsychopharmacol 1995; 13 (4): 269-93.
69. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991; 251 (4989): 85-7.
70. Koyuncuoglu H, Nurten A, Yamanturk P, Nurten R. The importance of the number of NMDA receptors in the development of supersensitivity or tolerance to and dependence on morphine. Pharmacol Res 1999; 39 (4): 311-9.
71. Kolesnikov YA, Ferkany J, Pasternak GW. Blockade of mu and kappa 1 opioid analgesic tolerance by NPC17742, a novel NMDA antagonist. Life Sci 1993;53 (19): 1489-94.
72. Beczkowska IW, Gracy KN, Pickel VM, Inturrisi CE. Detection of delta opioid receptor and N-methyl-D-aspartate receptor-like immunoreactivity in retinoic acid-differentiated neuroblastoma x glioma (NG108-15) cells.J Neurosci Res 1997; 47 (1): 83-9.
73.Bullitt E, Lee CL, Light AR, Willcockson H. The effect of stimulus duration on noxious-stimulus induced c-fos expression in the rodent spinal cord.Brain Res 1992; 580 (1-2): 172-9.
74. Bullitt E. Induction of c-fos-like protein within the lumbar spinal cord and thalamus of the rat following peripheral stimulation. Brain Res 1989;493 (2): 391-7.
75. Abbadie C, Besson JM. c-fos expression in rat lumbar spinal cord during the development of adjuvant-induced arthritis. Neuroscience 1992; 48 (4):985-93.
76. Abbadie C, Lombard MC, Morain F, Besson JM. Fos-like immunoreactivity in the rat superficial dorsal horn induced by formalin injection in the forepaw: effects of dorsal rhizotomies. Brain Res 1992; 578 (1-2): 17-25.
77. Presley RW, MenetreyD, Levine JD, Basbaum AI. Systemic morphine suppresses noxious stimulus-evoked Fos protein-like immunoreactivity in the rat spinal cord. J Neurosci 1990; 10 (1): 323-35.
78.Dolan S, Field LC, Nolan AM. The role of nitric oxide and prostaglandin signaling pathways in spinal nociceptive processing in chronic inflammation. Pain 2000; 86 (3): 311-20.
79.Haley JE, Sullivan AF, Dickenson AH. Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Res 1990; 518 (1-2): 218-26.
80.Herdegen T, Kovary K, Leah J, Bravo R. Specific temporal and spatial distribution of JUN, FOS, and KROX-24 proteins in spinal neurons following noxiouse transsynaptic stimulation. J Comp Neurol 1991; 313 (1): 178-91.
81. Labuz D, Chocyk A, Wedzony K, Toth G, Przewlocka B. Endomorphine-2, deltorphin II and their analogs suppress formalin-induced nociception and c-Fos expression in the rat spinal cord. Life Sci 2003; 73 (4): 403-12.
82.Tolle TR, Castro-Lopes JM, Coimbra A, Zieglgansberger W. Opiates modify induction of c-fos proto-oncogene in the spinal cord of the rat followingnoxious stimulation. Neurosci Lett 1990; 111 (1-2): 46-51.
83．曹君利，曾因明，张励才．NO参与介导吗啡戒断大鼠脊髓神经元敏感化．生理学报2001：53(1)：75-84．
84. Handy RL, Moore PK. A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity. Br J Pharmacol 1998; 123 (6): 1119-26.
85. Ayers NA, Kapas L, Krueger JM. The inhibitory effects of N-omega-nitro-L-arginine methyl ester on nitric oxide synthase activity vary among brain regions in vivo but not in vitro. Neurochem Res 1997; 22 (1): 81-6.
86. Malmberg AB, Yaksh TL. The effect of morphine on formalin-evoked behaviour and spinal release of excitatory amino acids and prostaglandin E2 using microdialysis in conscious rats. Br J Pharmacol 1995; 114 (5): 1069-75.
87. Lawand NB, McNearney T, Westlund KN. Amino acid release into the knee joint: key role in nociception and inflammation. Pain 2000; 86 (1-2): 69-74.
88. Malmberg AB, Yaksh TL. Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: a microdialysis study in unanesthetized rats. J Neurosci 1995; 15(4): 2768-76.
89. Mayer ML, Westbrook GL, Guthrie PB. Voltage-dependent block by Mg2+of NMDA responses in spinal cord neurons. Nature 1984; 309 (5965): 261-3.
90. Headley PM, Grillner S. Excitatory amino acids and synaptic transmission: the evidence for a physiological function. Trends Pharmacol Sci 1990; 11 (5): 205-11.
91. Yaksh TL. Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature 1980; 286 (5769): 155-7.
92. Budd PC, Nicholls DG, McLaughlin M. The target of PKC induced suppression of adenosine inhibition of glutamate release from synaptosomes is downstream of the A1 receptor and G-protein coupling. Biochem Soc Trans 1996; 24 (3): 429S.
93. Sanchez-Prieto J, Budd PC, Herrero I, Vazquez E, Nicholls DG. Presynaptic??receptors and the control of glutamate exocytosis. Trends Neurosci 1996; 19 (6): 235-9.
94. Coderre TJ. Contribution of protein kinase C to central sensitization and persistent pain following tissue injury. Neurosci Lett 1992; 140 (2): 181-4.
95. Wen ZH, Chang YC, Cherng CH, Wang JJ, rao PL, Wong CS. Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats. Brain Res 2004; 995 (2): 253-9.
96. Ferreira SH, Lorenzetti BB. Glutamate spinal retrograde sensitization of primary sensory neurons associated with nociception. Neuropharmacology 1994; 33 (11): 1479-85.
97. Ozawa T, Nakagawa T, Shige K, Minami M, Satoh M. Changes in the expression of glial glutamate transporters in the rat brain accompanied with morphine dependence and naloxone-precipitated withdrawal. Brain Res 2001; 905 (1-2): 254-8.
98. Yrotti O, Peng JB, Dunlop J, Hediger MA. Inhibition of the glutamate transporter EAAC1 expressed in Xenopus oocytes by phorbol esters. Brain Res 2001; 914 (1-2): 196-203.
99. Mao J, Sung B, Ji RR, Elm G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002; 22 (18): 8312-23.
100. Heinzen EL, Pollack GM. The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice. Biochem Pharmacol 2004; 67 (4): 735-41.
101．刘惠芬，周文华，谢小虎，曹君利，顾钧，杨国栋．M受体对吗啡戒断大鼠脊髓和脑干NMDA受体基因表达及中脑导水管周围灰质中谷氨酸释放的调节．生理学报2004：56(1)：95-100．
102. Zhu H, Brodsky M, Gorman AL, and Inturrisi CE Region-specific changes in NMDA receptor mRNA induced by chronic morphine treatment are prevented by the co-administration of the competitive NMDA receptor antagonist LY274614.??Brain Res Mol 8rain Res 2003; 114 (1): 154-62.
103. Leza JC, Lizasoain I, San-Martin-Clark O, Lorenzo P. Morphine-induced changes in cerebral and cerebellar nitric oxide synthase activity. Eur J Pharmacol 1995; 285 (1): 95-8.
104. Elliott K, Minami N, Kolesnikov YA, Pasternak GW, Inturrisi CE. The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. Pain 1994; 56 (1): 69-75.
105. Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001; 81 (1): 299-343.
106．曹君利，刘惠芬，周文华，杨国栋，张励才，曾因明．鞘内注射NOS反义寡核苷酸抑制吗啡戒断大鼠脊髓和脑干NADA1A受体mRNA表达的增加．生理学报2001：53(1)：27-31．
107. Soares-Mota M, Henze I, Mendez-Otero R. Nitric oxide synthase-positive neurons in the rat superior colliculus: colocalization of NOS with NMDAR1 glutamate receptor, GABA, and parvalbumin. J Neurosci Res 2001; 64 (5): 501-7.1.MillanMJ. The induction of pain: an integrative review. Prog Neurobiol 1999;57 (1): 1-164.
2. Dubner R, Bennett GJ. Spinal and trigeminal mechanisms of nociception. Annu Rev Neurosci 1983; 6; 381-418.
3.Sherrington CS. The integrative action of the nervous system. Scribner,New York 1906.
4. Lembech F, Donnerer J. The wide spectrum of function of capsaicin-sensitive nociceptive afferents. In; sicuteri F, Advances in pain research and therapy. Raven Press Ltd, New York 1992; 45-53.
5.Ren K. Primary afferents and inflammatory hyperexcitability. Pain 1996;67 (1): 1-2.
6. Bessou P, Perl ER. Reponse of cutaneous sensory units with unmyelinated fibers to noxious stimuli. J Neurophysiol 1969; 32 (6): 1025-43.
7. Van Hees J. Human C-fiber input during painfull and nonpainful skin stimulation with radiant heat. In:Bonica JJ.Alble-Fessard DG (eds) Advances in pain research and therapy, vol 1. Raven, New York 1976; 35-40.
8. Cervero F. Sensory innervation of the viscera: peripheral basis of visceral pain. Physiol Rev 1994; 74 (1): 95-138.
9. Cervero F. Visceral pain: mechanisms of peripheral and central sensitization.Ann Med 1995; 27 (2): 235-9.
10. Gebhart GF. Visceral nociception: consequences, modulation and the future.Eur J Anaesthesiol 1995; 10: S24-7.
11. Pitcher GM, Henry JL. Cellular mechanisms of hyperalgesia and spontaneous pain in a spinalized rat model of peripheral neuropathy: changes in myelinated afferent inputs implicated. Eur J Neurosci 2000; 12(6): 2006-20.
12. Baumann TK, Simone DA, Shain CN, LaMotte RH. Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol, 1991, 66 (1):??212-27.
13. Ckube MA, Ochoa J, Torebjork HE. Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain 1989; 112 (Pt 3): 621-47.
14. Torebjork HE, Linberg LE, Lamotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 1992; 448: 765-80.
15. Ren K, Williams GM, Ruda MA, Dubner R. Inflammation and hyperalgesia in rats neonatally treated with capsaicin:effects on two classes of nociceptive neurons in the superficial dorsal horn. Pain 1994; 59 (2): 287-300.
16. Herrero JF, de la Rubia PG, Cervero F. Wind-up of spinal cord neurons is influenced by inflammation, spinalization, endogenous opiods and type of stimulation. Soc Neurosci Abstr 1995; 21: 1407.
17. Ma QP , Woolf JC. Noxious stimuli induce an N-methyl-D-aspartate receptor-dependent hypersensitivity of the flexion withdrawal reflexes to touch: implications for the treatment of mechanical allodynia. Pain 1995;61 (3) : 383-90.
18. Neugerbauer VT. NMDA and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat' s knee joint. J Neurophsiology 1993; 44 (4): 1365-77.
19. LaMotte RH, Shain CN, Simone DA, Tsai EF. Neurogenic hyperalgesia: Psychophysiol studies of underlying mechanism. J Neurophsiol 1991; 66 (1):190～211.
20. Woolf CJ. The dorsal horn: state-dependent sensory processing and the generation of pain. In: Wall PD, Mealzack R, ed. Textbook of pain. Edinburgh:Churchill Livingstone 1994; 101.
21. Price DD, Hayes RL, Ruda M, Dubner R. Spatial and temporal transformations of input to spinothalamic tract neurons and their relation to somatic sensations. J Neurophysiol 1978; 41 (4): 933-47.
22.You HJ, Dahl Morch C, Chen J, Arendt-Nielsen L. Simultaneous recordings of wind-up of paired spinal dorsal horn nociceptive neuron and nociceptive??flexion reflex in rats. Brain Res 2003; 960 (1-2): 235-45.
23.Culberson JL, Haines DE, Kimmel DL, Brown PB. Contralateral projection of primary afferent fibers to mammalian spinal cord. Exp Neurol 1979; 64 (1):83-97.
24. SugiuraY, Lee CL, Perl ER. Central projections of identified, unmyelinated (C) afferent fibers innervating mammalian skin. Science 1986; 234(4774):358-61.
25. Biella G, Riva L, Sotgiu ML. Interaction between neurons in different laminae of the dorsal horn of the spinal cord. A correlation study in normal and neuropathic rats. Eur J Neurosci 1997; 9 (5): 1017-25.
26. Coggeshall RE, Carlton SM. Receptor localization in the mammalian dorsal horn and primary afferent neurons. Brain Res Rev 1997; 24 (1): 28-66.
27. Takakusaki K, Kohyama J, Matsuyama K, Mori S. Medullary reticulospinal tract mediating the generalized motor inhibition in cats: parallel inhibitory mechanisms acting on motoneurons and on interneuronal transmission in reflex pathways. Neurosci 2001; 103 (2): 511-27.
28. Bao L, Wang HF, Cai HJ, et al.. Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord. Eur J Neurosci 2002; 16 (2): 175-85.
29. Kawasaki Y, Kohno T, Zhuang ZY, et al. Ionotropic and metabotropic receptors,protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci 2004;24 (38): 8310-21.
30. Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA. Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci 2002; 22 (20): 9086-98.
31. Yang K, Ma WL, Feng YP, Dong YX, Li YQ. Origins of GABA (B) receptor-like immunoreactive terminals in the rat spinal dorsal horn. Brain Res Bull 2002;58 (5): 499-507
32.Hama AT, Fritschy JM, Hammond DL. Differential distribution of (GABA) A receptor subunits on bulbospinal serotonergic and nonserotonergic neurons of the ventromedial medulla of the rat. J Comp Neurol 1997; 384 (3): 337-48.
33.Todd AJ , Spike RC. The localization of classical transmitters and neuropeptides within neurons in laminae I—III of the mammalian spinal dorsal horn. Prog Neurobiol 1993; 41 (5): 609-45.
34.Soares-Mota M, Henze I, Mendez-Otero R. Nitric oxide synthase-positive neurons in the rat superior colliculus: colocalization of NOS with NMDAR1 glutamate receptor, GABA, and parvalbumin. J Neurosci Res. 2001; 64 (5):501-7.
35.Pitcher GM , Henry JL. Nociceptive response to innocuous mechanical stimulation is mediated via myelinated afferents and NK-1 receptor activation in a rat model of neuropathic pain. Exp Neurol 2004; 186 (2):173-97.
36. Valtschanoff JG, Weinberg RJ, Rustioni A. Central release of tracer after noxious stimulation of the skin suggests non-synaptic signaling by unmyelinated fibers. Neurosci 1995; 64 (4): 851-4.
37.Millan MJ, Perrin-Monneyron S. Potentiation of fluoxetine-induced penile erections by combined blockade of 5-HT1A and 5-HT1B receptors. Eur J Pharmacol 1997; 321 (3): R11-3.
38.Kolhekar R, Murphy S , Gebhart GF. Thalamic NMDA receptors modulate inflammation-produced hyperalgesia in the rat. Pain 1997; 71 (1): 31-40.
39.Mayer ML, Westbrook GL. The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 1987; 28 (3): 197-276.
40. Vetter G, Geisslinger G, Tegeder I. Release of glutamate, nitric oxide and prostaglandin E2 and metabolic activity in the spinal cord of rats following peripheral nociceptive stimulation. Pain 2001; 92 (1-2): 213-8.
41.Borszcz GS, Johnson CP, Williams DH. Increases in vocalization and motor reflex thresholds generated by the intrathecal administration of serotonin or norepinephrine. Behav Neurosci 1996; 110 (4): 809-22.
42. Gao K, Mason P. Serotonergic Raphe magnus cells that respond to noxious tail heat are not ON or OFF cells. J Neurophysiol 2000; 84 (4): 1719-25.
43. Antal M, Petko M, Polgar E, Heizmann CW, Storm-Mathisen J. Direct evidence of an extensive GABAergic innervation of the spinal dorsal horn by fibres descending from the rostral ventromedial medulla. Neurosci 1996; 73 (2):509-18.
44. Wang D, Li YQ, Li JL, KanekoT, Nomura S, MizunoN. Gamma-aminobutyric acid-and glycine-immunoreactive neurons postsynaptic to substance P-immunoreactive axon terminals in the superficial layers of the rat medullary dorsal horn. Neurosci Lett 2000; 288 (3): 187-90.
45. Chen YP, Chen SR, Pan HL. Systemic morphine inhibits dorsal horn projection neurons through spinal cholinergic system independent of descending pathways. J Pharmacol Exp Ther 2005; 314 (2): 611-7.
46.Xie JY, Herman DS, Stiller CO, et al. Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. J Neurosci 2005; 25 (2): 409-16.
47. Almeida A, Tjolsen A, Lima D, Coimbra A, Hole K. The medullary dorsal reticular nucleus facilitates acute nociception in the rat. Brain Res Bull 1996;39 (1): 7-15.
48.Bardin L, Jourdan D, Alloui A, Lavarenne J, Eschalier A. Differential influence of two serotonin 5-HT3 receptor antagonists on spinal serotonin-induced analgesia in rats. Brain Res 1997; 765 (2): 267-72.
49.Urban MO, Smith DJ, Gebhart GF. Involvement of spinal cholecystokininB receptors in mediating neurotensin hyperalgesia from the medullary nucleus raphe magnus in the rat. J Pharmacol Exp Ther 1996; 278 (1): 90-6.
50. Abacioglu N, Tunctan B, Akbulut E, Cakici I. Participation of the components of L-arginine/nitric oxide/cGMP cascade by chemically-induced abdominal constriction in the mouse. Life Sci 2000; 67 (10): 1127-37.
51.Okuda K, Sakurada C, Takahashi M, Yamada T, Sakurada T. Characterization of nociceptive responses and spinal releases of nitric oxide metabolitesand glutamate evoked by different concentrations of formalin in rats. Pain 2001; 92 (1-2): 107-15.
52.Azkue JJ, Knopfel T, Kuhn R, Mateos JM, Grandes P. Distribution of the metabotropic glutamate receptor subtype mGluR5 in rat midbrain periaqueductal grey and relationship with ascending spinofugal afferents.Neurosci Lett 1997; 228 (1): 1-4.
53. Eaton SA, Salt TE. Role of N-methyl-D-aspartate and metabotropic glutamate receptors in corticothalamic excitatory postsynaptic potentials in vivo.Neurosci 1996; 73 (1): 1-5.
54.ZouX, Lin Q, Willis WD. Enhanced phosphorylation of NMDA receptor 1 subunits in spinal cord dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. J Neurosci 2000; 20 (18): 6989-97.
55. Popratiloff A, Rustioni A, Weinberg RJ. Heterogeneity of AMPA receptors in the dorsal column nuclei of the rat. Brain Res 1997; 754 (1-2): 333-9.
56. Elena Erro M, Lanciego JL, Gimenez-Amaya JM. Re-examination of the thalamostriatal projections in the rat with retrograde tracers. Neurosci Res 2002;42 (1): 45-55.
57. Li JL, Ding YQ, Shigemoto R, Mizuno N. Distribution of trigeminothalamic and spinothalamic-tract neurons showing substance P receptor-like immunoreactivity in the rat. Brain Res 1996; 719 (1-2): 207-12.
58. Li JL, Mizuno N. Parabrachial nucleus neurons providing axons to both the thalamus and the spinal cord in the rat. Brain Res 1997; 745 (1-2): 321-7.
59. Yasui Y, Yokota S, Ono K, Tsumori T. Projections from the red nucleus to the parvicellular reticular formation and the cervical spinal cord in the rat, with special reference to innervation by branching axons. Brain Res 2001; 923 (1-2): 187-92.
60.Nichols ML, Lopez Y, Ossipov MH, Bian D, Porreca F. Enhancement of the antiallodynic and antinociceptive efficacy of spinal morphine by antisera to dynorphin A (1-13) or MK-801 in a nerve-ligation model of peripheral neuropathy. Pain 1997; 69 (3): 317-22.
61.Brauneis U, Oz M, Peoples RW, Weight FF, Zhang L. Differential sensitivity of recombinant N-methyl-D-aspartate receptor subunits to inhibition by dynorphin. J Pharmacol Exp Ther 1996; 279 (3): 1063-8.
62. PeyronR, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000) . Neurophysiol Clin 2000; 30(5): 263-88.
63. Derbyshire SW, Jones AK, Gyulai F, Clark S, Townsend D, Firestone LL. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 1997; 73 (3): 431-45.
64. Derbyshire SW, Jones AK, Creed F, et al. Cerebral responses to noxious thermal stimulation in chronic low back pain patients and normal controls. Neuroimage 2002; 16 (1): 158-68.
65. Bonham AC, Chen CY. Glutamatergic neural transmission in the nucleus tractus solitarius: N-methyl-D-aspartate receptors. Clin Exp Pharmacol Physiol 2002; 29 (5-6): 497-502.
66.Liaw WJ, Stephens RL Jr, Binns BC, et al. Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 2005; 115 (1-2): 60-70.
67. Peng YB, Wu J, Willis WD, Kenshalo DR. GABA (A) and 5-HT (3) receptors are involved in dorsal root reflexes: possible role in periaqueductal gray descending inhibition. J Neurophysiol 2001; 86 (1): 49-58.
68.Do KQ, Binns KE, Salt TE. Release of the nitric oxide precursor, arginine,from the thalamus upon sensory afferent stimulation, and its effect on thalamic neurons in vivo. Neurosci 1994; 60 (3): 581-6.
69. Terayama R, Guan Y, Dubner R, Ren K. Activity-induced plasticity in brain stem pain modulatory circuitry after inflammation. Neuroreport 2000; 11(9): 1915-9.
70.Guan Y, Terayama R, Dubner R, Ren K. Plasticity in excitatory amino acid receptor-mediated descending pain modulation after inflammation. J Pharmacol Exp Ther 2002; 300 (2): 513-20.
71.Bredt DS and Snyder SH. Isolation of nitric oxide systhase , a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 1990; 87 (2): 682-5.
72. Bredt DS, Glatt CE, Hwang PM, Fotuhi M, Dawson TM, Snyder SH. Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 1991; 7 (4):615-24.
73. Forstermann U, Schmidt HH, Pollock JS, et al. Isoforms of nitric oxide synthase. Characterization and purification from different cell types. Biochem Pharmacol 1991; 42 (10): 1849-57.
74. Solodkin A, Traub RJ, Gebhart GF. Unilateral hindpaw inflammation produces a bilateral increase in NADPH-diaphorase histochemical staining in the rat lumbar spinal cord. Neurosci 1992; 51 (3): 495-9.
75. Fiallos-Estrada CE, Kummer W, Mayer B, Bravo R, Zimmermann M, Herdegen T. Long-lasting increase of nitric oxide synthase immunoreactivity ,NADPH-diaphorase reaction and c-JUN co-expression in rat dorsal root ganglion neurons following sciatic nerve transection. Neurosci Lett 1993;150 (2): 169-73.
76.Herdegen T, Kovary K, Leah J, Bravo R. Specific temporal and spatial distribution of JUN, FOS, and KROX-24 proteins in spinal neurons following noxiouse transsynaptic stimulation. J Comp Neuro 1991; 313 (1): 178-91.
77.Barinaga M. Is nitric oxide the "retrograde messenger"? Science 1991;254 (5036): 1296-7.
78. Bult H, Boeckxstaens GE, Pelckmans PA, Jordaens FH, Van Maercke YM, Herman AG. Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature 1990; 345 (6273): 346-7.
79. McCall T and VallanceP. Nitric oxide take center-stage with newly defined roles, Trendes Pharmacol Sci 1992; 13 (1): 1-6.
80. Kitto KF, Haley JE, Wilcox GL. Involvement of nitric oxide in spinally mediated hyperalgesia in the mouse. Neurosci Lett 1992; 148 (1-2): 1-5.
81. Lin Q, Wu J, Peng YB, Cui M, Willis WD. Inhibition of primate spinothalamictract neurons by spinal glycine and GABA is modulated by guanosine 3', 5'-cyclic monophosphate. J Neurophysiol 1999; 81 (3): 1095-103.
82. Lin Q, Peng YB, Willis WD. Role of GABA receptor subtypes in inhibition of primate spinothalamic tract neurons : difference between spinal and periaqueductal gray inhibition. J Neurophysiol 1996 ; 75 (1): 109-23.
83. Knowles RG, Merrett M, Salter M, MoncadaS. Differential induction of brain,lung and liver nitric oxide synthase by endotoxin in the rat. Biochem J 1990;270 (3): 833-6.
84. Knowles RG, PalaciosM, Palmer RM, MoncadaS, Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci USA 1989;86 (13): 5159-62.
85. Vincent SR, Hope BT. Neurons that say NO. Trends Neurosci 1992; 15 (3):108-13.
86.Pan HL, Chen SR, Eisenach JC. Intrathecal clonidine alleviates allodynia in neuropathic rats: interaction with spinal muscarinic and nicotinic receptors. Anesthesiology 1999; 90 (2): 509-14.
87. Xu Z, Chen SR, Eisenach J, Pan HL. Role of spinal muscarinic and nicotinic receptors in clonidine-induced nitric oxide release in a rat model of neuropathic pain. Brain Res 2000; 861 (2): 390-8.
88.Peunova N , Enikolopov G. Amplification of calcium-induced gene transcription by nitric oxide in neuronal cells. Nature 1993; 364 (6436):450-3.
89.Ciani E, Guidi S, Bartesaghi R, Contestabile A. Nitric oxide regulates cGMP-dependent cAMP-responsive element binding protein phosphorylation and Bcl-2 expression in cerebellar neurons: implication for a survival role of nitric oxide. J Neurochem 2002; 82 (5): 1282-9.
90.Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.Nature 2002; 415 (6873): 793-8.
91.Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science. 1992; 256 (5060): 1217-21.
92.Mori H, Mishina M. Structure and function of the NMDA receptor channel.Neuropharmacology 1995; 34 (10): 1219-37.
93. Mayer ML, Westbrook GL, Guthrie PB. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurons. Nature 1984; 309 (5965): 261-3.
94.Mayer ML, Westbrook GL. Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones.J Physiol 1987; 394: 501-27.
95.East SJ and Garthwaite J, NMDA receptor activition in rat hippocampus induceds cyclic GMP formation through the L-arginine-nitric oxide pathway.Neurosci Lett 1991; 123 (1): 17-9.
96. Tao YX, Johns RA, Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw. Neurosc 2002; 112 (2): 439-46.
97. BredtDS, Snyder SH, Nitric oxide, a novel neuronal messenger. Neuron 1992;8 (1): 3-11.
98. Vikman KS, Duggan AW, Siddall PJ. Increased ability to induce long-term potentiation of spinal dorsal horn neurones in monoarthritic rats. Brain Res 2003; 990 (1-2): 51-7.
99.Pedersen LM, Lien GF, Bollerud I, Gjerstad J. Induction of long-term potentiation in single nociceptive dorsal horn neurons is blocked by the CaMKII inhibitor AIP. Brain Res 2005; 1041 (1): 66-71.
100. Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003; 26 (12):696-705.
101. Malenka RC, Nicoll RA. Learning and memory. Never fear, LTP is hear. Nature 1997; 390 (6660): 552-3.
102. Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989; 63 (2): 139-46.
103. Woolf CJ, Shortland P, Coggeshall RE. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 1992:355 (6355): 75-8.
104. Dubner R, Ruda MA, Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends Neurosci 1992; 15 (3): 96-103.
105. Meller ST, Dykstra C, Gebhart GF. Production of endogenous nitric oxide and activation of soluble guanylate cyclase are required for N-methyl-D-aspartate-produced facilitation of the nociceptive tail-flick reflex. Eur J Pharmacol 1992; 214 (1): 93-6.
106. Yamamoto T, Yaksh TL. Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve. Excitatory amino acid antagonists. Pain 1992; 49 (1): 121-8.
107. Collingridge GL, Blake JF, Brown MW, Bashir ZI, Ryan E. Involvement of excitatory amino acid receptors in long-term potentiation in the Schaffer collateral-commissural pathway of rat hippocampal slices. Can T Physiol Pharmacol 1991; 69 (7): 1084-90.
108. Headley PM, Grillner S. Excitatory amino acids and synaptic transmission: the evidence for a physiological function. Trends Pharmacol Sci 1990; 11 (5): 205-11.
109．钟敏．疼痛中枢敏感化的分子机制．《国外医学》麻醉学与复苏分册2000；21(3)：148-51．
110. Davidson EM, Coggeshall RE, Carlton SM. Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviors in the rat formalin test. Neuroreport 1997; 8 (4): 941-6.
111. Lawand NB, McNearney T, Westlund KN. Amino acid release into the knee joint: key role in nociception and inflammation. Pain 2000; 86 (1-2): 69-74.
112. Soliman AC, Yu JS, Coderre TJ. mGlu and NMDA receptor contributions to capsaicin-induced thermal and mechanical hypersensitivity. Neuropharmacology 2005; 48 (3): 325-32.113.Ro JY, Nies M, Zhang Y. The role of peripheral N-methyl-D-aspartate receptors in muscle hyperalgesia. Neuroreport 2005; 16 (5): 485-9.
114. Kawamata T, Omote K. Activation of spinal N-methyl-D-aspartate receptors stimulates a nitric oxide/cyclic guanosine 3, 5-monophosphate/glutamate release cascade in nociceptive signaling. Anesthesiology 1999; 91 (5):1415-24.
115. North RA, Williams JT, Surprenant A, Christie MJ. Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. Proc Natl Acad Sci USA 1987; 84 (15): 5487-91.
116.Connor M, Vaughan CW, Chieng B, Christie MJ. Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro. Br J Pharmacol 1996; 119 (8): 1614-8.
117. Rusin KI, Moises HC. Mu-opioid and GABA (B) receptors modulate different types of Ca2+ currents in rat nodose ganglion neurons. Neurosci 1998;85 (3): 939-56.
118. Williams JT, Christie MJ, Manzoni 0. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001; 81 (1): 299-343. Review.
119. Kieffer BL. Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides. Cell Mol Neurobiol 1995; 15 (6): 615-35.
120.孙国勤,徐惠芳.阿片受体亚型研究进展.生命的化学 2000; 20 (3): 106-9.
121.Wang HQ, Kampine JP, Tseng LF. Antisense oligodeoxynucleotide to a delta-opioid receptor messenger RNA selectively blocks the antinociception induced by intracerebroventricularly administered delta-, but not mu-, epsilon- or kappa-opioid receptor agonists in the mouse.Neurosci 1996; 75 (2): 445-52.
122. Simonin F, Valverde 0, Smadja C, et al. Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain,impairs pharmacological actions of the selective kappa-agonist U-50, 488H and attenuates morphine withdrawal. EMBO J 1998 16; 17 (4):886-97.
123. Kress M, Guthmann C, Averbeck B, Reeh PW. Calcitonin gene-related peptide and prostaglandin E2 but not substance P release induced by antidromic nerve stimulation from rat skin in vitro. Neurosci 1999; 89 (1): 303-10.
124. BalletS, Mauborgne A, Benoliel JJ, et al. Olyarthritis-associated changes in the opioid control of spinal CGRP release in the rat. Brain Res 1998;796 (1-2): 198-208.
125.Georges F, Stinus L, Bloch B, Le Moine C. Chronic morphine exposure and spontaneous withdrawal are associated with modifications of dopamine receptor and neuropeptide gene expression in the rat striatum. Eur J Neurosci 1999; 11 (2): 481-90.
126. Shippenberg TS, Rea W. Sensitization to the behavioral effects of cocaine:modulation by dynorphin and kappa-opioid receptor agonists. Pharmacol Biochem Behav 1997; 57 (3): 449-55.
127.King MA, Bradshaw S, Chang AH, Pintar JE, Pasternak GW. Potentiation of opioid analgesia in dopamine2 receptor knock-out mice: evidence for a tonically active anti-opioid system. J Neurosci 2001; 21 (19): 7788-92.
128. Dalman FC, 0' Malley KL. kappa-Opioid tolerance and dependence in cultures of dopaminergic midbrain neurons. J Neurosci 1999; 19 (14): 5750-7.
129.Schuman EM, Madison DV. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 1991; 254 (5037): 1503-6
130. Majeed NH, Przewlocka B, Machelska H, Przewlocki R. Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice. Neuropharmacology 1994; 33 (2): 189-92.
131. Yamaguchi H, Naito H. Antinociceptive synergistic interaction between morphine and n-omega nitro-L-arginine methyl ester on thermal nociceptive tests in the rats. Can J Anaesth 1996; 43 (9): 975-81.
132.Benamar K, Xin L, Geller EB, Adler MW. Modulation of morphine analgesia by a nitric oxide synthase inhibitor microinjected into the periaqueductal gray in rats. Analgesia 2002; 6 (1-3): 7-10.
133. Przewlocki R, Machelska H, Przewlocka B. Inhibation of nitric oxide synthaseenhances morphine antinociception in the rat spinal cord. Life Sci 1993;53 (1): PL1-5.
134.Babey AM, Kolesnikov Y, Cheng J, Inturrisi CE, Trifilletti RR, Pasternak GW. Nitric oxide and opioid tolerance. Neuropharmacology 1994; 33 (11):1463-70.
135. Zek M, Uresin Y, Gungor M. Comparison of the effects of specific and nonspecific inhibition of nitric oxide synthase on morphine analgesia, tolerance and dependence in mice. Life Sci 2003; 72 (17): 1943-51.
136. Rauhala P , Idanpaan-Heikkila JJ , Tuominen RK , Mannisto PT. N-nitro-L-arginine attenuates development of tolerance to antinociceptive but not to hormonal effects of morphine. Eur J Pharmacol. 1994; 259 (1):57-64.
137. Pataki I, Telegdy G. Further evidence that nitric oxide modifies acute and chronic morphine actions in mice. Eur J Pharmacol 1998; 357 (2-3): 157-62.
138. Bhargava HN, BianJT, N (G) -nitro-L-arginine reverses L-arginine induced changes in morphine antinociception and distribution of morphine in brain regions and spinal cord of the mouse. Brain Research 1997; 749 (2): 351-3.
139. Kolesnikov YA, Pick CG, Pasternak GW. NG-nitro-L-arginine prevents morphine tolerance. Eur J Pharmacol 1992; 221 (2-3): 399-400.
140. Kolesnikov YA,, Pick CG, CiszewskaG, Pasternak GW. Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor.Proc Natl Acad Sci U S A 1993; 90 (11): 5162-6.
141. Xu JY, Tseng LF. Nitric oxide/cyclic guanosine monophosphate system in the spinal cord differentially modulates intracerebroventricularly administered morphine-and beta-endorphin-induced antinociception in the mouse. J Pharmacol Exp Ther 1995; 274 (1): 8-16.
142.Pelligrino DA Laurito CE Vade B Timothy R. Nitric Oxide Synthase Inhibition Modulates the Ventilatory Depressant and Antinociceptive Actions of Fourth Ventricular Infusions of Morphine in the Awake Dog. Anesthesiology. 1996; 85 (6): 1367-77.
143. Li XQ, Clark JD, Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. Brain research Molecular Brain Research 2001; 95 (1-2): 96-102.
144. Dunbar S, Yaksh TL. Effect of spinal infusion of L-NAME, a nitric oxide synthase inhibitor, on spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Neurosci Lett 1996; 207 (1): 33-6.
145. Heinzen EL, Pollack GM. The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice. Biochem Pharmacol 2004; 67 (4): 735-41.
146. Wong CS, Hsu MM, Chou YY, Tao PL, Tung CS. Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord. Br J Anaesth 2000; 85 (4): 587-91.
147. Cuellar B, Fernandez AP, Lizasoain I, Moro MA, Lorenzo P, Bentura ML, Rodrigo J, Leza JC. Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal. Psychopharmacology 2000; 148 (1): 66-73.
148．曹君利，曾因明，张励才．NO参与介导吗啡戒断大鼠脊髓神经元敏感化．生理学报2001：53(1)：75-84．
149. Machelska H, Ziolkowska B, Mika J, Przewlocka B, Przewlocki R. Chronic morphine increases biosynthesis of nitric oxide synthase in the rat spinal cord. Neuroreport 1997; 8 (12): 2743-7.
150. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991; 251 (4989): 85-7.
151. Wen ZH, Chang YC, Cherng CH, Wang JJ, Tao PL, Wong CS. Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats. Brain Res 2004; 995 (2): 253-9.
152. Beczkowska IW, Gracy KN, Pickel VM, Inturrisi CE. Detection of delta opioid receptor and N-methyl-D-aspartate receptor-like immunoreactivity in retinoic acid-differentiated neuroblastoma x glioma (NG108-15) cells. J Neurosci Res 1997; 47 (1): 83-9.153. Dunbar SA, Pulai IJ. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat. J Pharmacol Exp Ther 1998; 284 (2): 678-86.
154. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002; 22 (18): 8312-23.
155. Koyuncuoglu H, Nurten A, Yamanturk P, Nurten R. The importance of the number of NMDA receptors in the development of supersensitivity or tolerance to and dependence on morphine. Pharmacol Res 1999; 39 (4): 311-9.
156. Watanabe C, Okuda K, Sakurada C, Ando R, Sakurada T, Sakurada S. Evidence that nitric oxide-glutamate cascade modulates spinal antinociceptive effect of morphine: a behavioural and microdialysis study in rats. Brain Res 2003; 990 (1-2): 77-86.
157. Liang DY, Clark JD. Modulation of the NO/CO-cGMP signaling cascade during chronic morphine exposure in mice. Neurosci Lett 2004; 365 (1): 73-7.
158. Machelska H, Labuz D, Przewlocki R, Przewlocka B. Inhibition of nitric oxide synthase enhances antinociception mediated by mu, delta and kappa opioid receptors in acute and prolonged pain in the rat spinal cord. J Pharmacol Exp Ther 1997; 282 (2): 977-84.
159. Bhargava HN. Diversity of agents that modify opioid tolerance, physical dependence , abstinence syndrome , and self-administrative behavior. Pharmacol Rev 1994; 46 (3): 293-324.
160. Chapman V, Dickenson AH. The combination of NMDA antagonism and morphine produces profound antinociception in the rat dorsal horn. Brain Res 1992;573 (2): 321-3.
161.Coderre TJ. Contribution of protein kinase C to central sensitization and persistent pain following tissue injury. Neurosci Lett 1992; 140 (2):181-4.
162.Budd DC, Nicholls DG, McLaughlin M. The target of PKC induced suppression of adenosine inhibition of glutamate release from synaptosomes isdownstream of the Al receptor and G-protein coupling. Biochem Soc Trans 1996; 24 (3): 429S.
163. Lopez-Bayghen E, Ortega A. Glutamate-dependent transcriptional regulation of GLAST: role of PKC. J Neurochem 2004; 91 (1): 200-9.
2. Schuman EM, Madison DV. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 1991; 254 (5037): 1503-6.
3.Doursout MF, Liang Y, Chelly JE. NOS inhibitors exhibit antinociceptive properties in the rat formalin test. Can J Anaesth 2003; 50 (9): 909-16.
4.Yamaguchi H, Naito H. Antinociceptive synergistic interaction between morphine and n-omega nitro-L-arginine methyl ester on thermal nociceptive tests in the rats. Can J Anesth 1996; 43 (9): 975-81.
5. Przewlocki R, Machelska H, Przewlocka B. Inhibation of nitric oxide synthase enhances morphine antinociception in the rat spinal cord. Life Sci 1993;53 (1): PL1-5.
6. Majeed NH, Przewlocka B, Machelska H, Przewlocki R. Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice. Neuropharmacology 1994; 33 (2): 189-92.
7. Zek M, Uresin Y, Gungor M. Comparison of the effects of specific and nonspecific inhibition of nitric oxide synthase on morphine analgesia,tolerance and dependence in mice. Life Sci 2003; 72 (17): 1943-51.
8.Benamar K, Xin L, Geller EB, Adler MW. Modulation of morphine analgesia by a nitric oxide synthase inhibitor microinjected into the periaqueductal gray in rats. Analgesia 2002; 6 (1-3): 7-10.
9. Abacioglu N, Tunctan B, Akbulut E, Cakici I. Participation of the components of L-arginine/nitric oxide/cGMP cascade by chemically-induced abdominal constriction in the mouse. Life Sci 2000; 67 (10): 1127-37.
10. Pataki I, Telegdy G. Further evidence that nitric oxide modifies acute and chronic morphine actions in mice. Eur J Pharmacol 1998; 357 (2-3): 157-62.
11. Liang DY, Clark JD. Modulation of the NO/CO-cGMP signaling cascade during chronic morphine exposure in mice. Neurosci Lett 2004; 365 (1): 73-7.
12. Bhargava HN, Bian JT. N (G) -nitro-L-arginine reverses L-arginine induced changes in morphine antinociception and distribution of morphine in brain regions and spinal cord of the mouse. Brain Res 1997; 749 (2): 351-3.
13. Dunbar S, Yaksh TL. Effect of spinal infusion of L-NAME, a nitric oxide synthase inhibitor, on spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Neurosci Lett 1996; 207 (1): 33-6.
14.Harris JA. Using c-fos as a neural marker of pain. Brain Res Bull 1998;45 (1): 1-8.
15. Dubner R, Ruda MA. Activity-dependent neuronal plasticity following tissue injury and inflammation (Review) . Trends Neurosci 1992; 15 (3): 96-103.
16. Honor P, Buritova J, Besson JM. Carrageenin-evoked c-Fos expression in rat lumbar spinal cord: the effects of indomethacin. Eur J Pharmacol 1995;272 (2-3): 249-59.
17. Hunter JC, Woodburn VL, Durieux C, Pettersson EK, Poat JA, Hughes J. C-fos antisense oligodeoxynucleotide increases formalin-induced nociception and regulates preprodynorphin expression. Neurosci 1995; 65 (2): 485-92.
18. Garthwaite J, Garthwaite G, Palmer RM, Moncada S. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol 1989; 172 (4-5): 413-6.
19. Bredt DS, Snyder SH. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Nat 1 Acad Sci USA 1989; 86 (22): 9030-3.
20. East SJ, Garthwaite J. NMDA receptor activition in rat hippocampus induceds cyclic GMP formation through the L-arginine-nitric oxide pathway. Neurosci Lett 1991; 123 (1): 17-9.
21.Mayer ML, Westbrook GL. The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 1987; 28 (3): 197-276. Review.
22. Vetter G, Geisslinger G, Tegeder I. Release of glutamate, nitric oxide and prostaglandin E2 and metabolic activity in the spinal cord of rats following peripheral nociceptive stimulation. Pain 2001; 92 (1-2): 213-8.
23. Watanabe C, Okuda K, Sakurada C, Ando R, Sakurada T, Sakurada S. Evidence that nitric oxide-glutamate cascade modulates spinal antinociceptive effect of morphine: a behavioural and microdialysis study in rats. Brain Res 2003: 990 (1-2): 77-86.
24. Skilling SR, Smullin DH, Beitz AJ, Larson AA. Extracellular amino acid concentrations in the dorsal spinal cord of freely moving rats following veratridine and nociceptive stimulation. JNeurochem 1988; 51 (1): 127-32.
25. Machelska H, Ziolkowska B, Mika J, Przewlocka B, Przewlocki R. Chronic morphine increases biosynthesis of nitric oxide synthase in the rat spinal cord. Neuroreport 1997; 8 (12): 2743-7.
26. Cuellar B, Fernandez AP, Lizasoain I, Moro MA, Lorenzo P, Bentura ML, Rodrigo J, Leza JC. Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal. Psychopharmacology 2000; 148 (1): 66-73.
27. Wong CS, Hsu MM, Chou YY, Tao PL, Tung CS. Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord. Br J Anaesth 2000; 85 (4): 587-91.
28. Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977; 4 (2): 161-74.
29. Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. The formalin test: an evaluation of the method. Pain 1992; 51 (1): 5-17.
30. Rosland JH, Tjolsen A, Maehle B, Hole K. The formalin test in mice: effect of formalin concentration. Pain 1990; 42 (2): 235-42.
31. Sakurada C, Sugiyama A, Nakayama M, Yonezawa A, Sakurada S, Tan-No K, Kisara K, Sakurada T. Antinociceptive effect of spinally injected L-NAME on the acute nociceptive response induced by low concentrations of formalin. Neurochem Int 2001; 38 (5): 417-23.
32．李淑琴，李文斌，孙晓彩，李清军，陈晓玲，艾洁．MK-801抑制福尔马林实验引起的大鼠脊髓背角环氧合酶-2的表达．生理学报2004：56(1)：66-72．
33．徐叔云，卞如濂，陈修 主编．药理实验方法学 第三版．人民卫生出版社 884-5．34.Dickenson AH, Sullivan AF. Peripheral origins and central modulation of subcutaneous formalin-induced activity of rat dorsal horn neurones. Neurosci Lett 1987; 83 (1-2): 207-11.
35. Dickenson AH, Sullivan AF. Subcutaneous formal in-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain 1987; 30 (3): 349-60.
36. Puig S, Sorkin LS. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 1996; 64 (2):345-55.
37. Hunskaar S, Hole K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 1987; 30 (1): 103-14.
38. Okuda K, Sakurada C, Takahashi M, Yamada T, Sakurada T. Characterization of nociceptive responses and spinal releases of nitric oxide metabolites and glutamate evoked by different concentrations of formalin in rats. Pain 2001; 92 (1-2): 107-15.
39.Davidson EM, Coggeshall RE, Carlton SM. Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviors in the rat formalin test. Neuroreport 1997; 8 (4): 941-6.
40. Malmberg AB, Gilbert H, McCabe RT, Basbaum AI. Powerful antinociceptiveeffects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T. Pain 2003; 101 (1-2): 109-16.
41. Chapman V, Haley JE, Dickenson AH. Electrophysiologic analysis of preemptive effects of spinal opioids on N-methyl-D-aspartate receptor-mediated events. Anesthesiology 1994; 81 (6): 1429-35.
42.Sakurada T, Sugiyama A, Sakurada C, Tan-No K, Yonezawa A , Sakurada S,Kisara K. Effect of spinal nitric oxide inhibition on capsaicin-induced nociceptive response. Life sci. 1996; 59 (11) :921-30.
43.Abbott FV, Melzack R, Leber BF Morphine analgesia and tolerance in the tail-flick and formalin tests: dose-response relationships. Pharmacol Biochem Behav 1982; 17 (6): 1213-9.
44.Babey AM, Kolesnikov Y, Cheng J, Inturrisi CE, Trifilletti RR, Pasternak GW. Nitric oxide and opioid tolerance. Neuropharmacology 1994; 33 (11):1463-70.
45.Rauhala P , Idanpaan-Heikkila JJ , Tuominen RK , Mannisto PT.N-nitro-L-arginine attenuates development of tolerance to antinociceptive but not to hormonal effects of morphine. Eur J Pharmacol 1994; 259 (1):57-64.
46.Wang XM, Yan JQ, Zhang KM, Mokha SS. Role of opioid receptors (mu, delta 1, delta 2)in modulating responses of nociceptive neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in the rat. Brain Res 1996; 739 (1-2): 235-43.
47.Chapman V, Dickenson AH. The combination of NMDA antagonism and morphine produces profound antinociception in the rat dorsal horn. Brain Res 1992;28; 573 (2): 321-3.
48.Meller ST, Gebhart GF. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 1993; 52 (2): 127-36
49.Wang H, Nei H, Zhang RX, Qiao JT. Peripheral nitric oxide contributes to both formalin- and NMDA-induced activation of nociceptors : an immunocytochemical study in rats. J Neurosci Res 1999; 57 (6): 824-9.
50.Malmberg AB, Yaksh TL. Spinal nitric oxide synthesis inhibition blocks NMDA-induced themal hyperalgesia and produces antinociception in the formalin test in rats. Pain 1993; 54 (3): 291-300.
51.Dambisya YM, Lee TL. Effects L-NG-nitro arginine methyl ester (L-NAME), L-NG-monomethyl arginine (L-NMMA) and L-arginine on the antinociceptive effects of morphine in mice. Methods Find Exp Clin Pharmacol 1995; 17 (9):577-82.
52.Meller ST, Pechman PS, Gebhart GF, Maves TJ. Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neurosci 1992; 50 (1): 7-10.
53.Moore PK, Oluyomi A0, Babbedge RC, Wallace P, Hart SL. L-NG-nitro argininemethyl ester exhibits antinociceptive activity in the mouse. Br J Pharmacol 1991; 102 (1): 198-202.
54. Roche AK, Cook M, Wilcox GL, Kajander KC. A nitric oxide synthesis inhibitor (L-NAME) reduces licking behavior and Fos-labeling in the spinal cord of rats during formalin-induced inflammation. Pain 1996; 66 (2-3):331-41.
55. Pelligrino DA, Laurito CE, VadeBoncouer TR. Nitric oxide synthase inhibition modulates the ventilatory depressant and antinociceptive actions of fourth ventricular infusions of morphine in the awake dog. Anesthesiology 1996;85 (6): 1367-77.
56. Xu JY, Tseng LF. Nitric oxide/cyclic guanosine monophosphate system in the spinal cord differentially modulates intracerebroventricularly administered morphine- and beta-endorphin-induced antinociception in the mouse. J Pharmacol Exp Ther 1995; 274 (1): 8-16.
57. Li XQ, Clark JD. Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. Brain Res Mol Brain Res 2001; 95 (1-2).- 96-102.
58.Tao YX, Johns RA. Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw. Neurosci 2002; 112 (2): 439-46.
59. Knowles RG, Palacios M, Palmer RM, Moncada S. Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase, Proc Natl Acad Sci USA 1989;86 (13): 5159-62.
60. Kolesnikov YA, Pick CG, Pasternak GW. NG-nitro-L-arginine prevents morphine tolerance. Eur J Pharmacol 1992; 221 (2-3): 399-400.
61.Dunbar SA, Pulai IJ. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat. J Pharmacol Exp Ther 1998; 284 (2): 678-86.
62. RohdeDS, DetweilerDJ, Basbaum AI. Formalin-evoked Fos expression in spinal cord is enhanced in morphine-tolerant rats. Brain Res 1997; 766 (1-2):93-100.
63. Sorkin LS. NMDA evokes an L-NAME sensitive spinal release of glutamate and citrulline. Neuroreport 1993; 4 (5): 479-82.
64.Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994; 14 (4): 2301-12.
65.Kitto KF, Haley JE, Wilcox GL.Involvement of nitric oxide in spinally mediated hyperalgesia in the mouse. Neurosci Lett 1992; 148 (1-2): 1-5.
66. MellerST, Dykstra C, Gebhart GF. Production of endogenous nitric oxide and activation of soluble guanylate cyclase are required for N-methyl-D-aspartate-produced facilitation of the nociceptive tail-flick reflex. Eur J Pharmacol 1992; 214 (1):93-6.
67.Dambisya YM, Lee TL. Role of nitric oxide in the induction and expression of morphine tolerance and dependence in mice. Br J Pharmacol 1996; 117(5): 914-8.
68. Herman BH, Vocci F, Bridge P. The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal.Medication development issues for opiate addiction. Neuropsychopharmacol 1995; 13 (4): 269-93.
69. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991; 251 (4989): 85-7.
70. Koyuncuoglu H, Nurten A, Yamanturk P, Nurten R. The importance of the number of NMDA receptors in the development of supersensitivity or tolerance to and dependence on morphine. Pharmacol Res 1999; 39 (4): 311-9.
71. Kolesnikov YA, Ferkany J, Pasternak GW. Blockade of mu and kappa 1 opioid analgesic tolerance by NPC17742, a novel NMDA antagonist. Life Sci 1993;53 (19): 1489-94.
72. Beczkowska IW, Gracy KN, Pickel VM, Inturrisi CE. Detection of delta opioid receptor and N-methyl-D-aspartate receptor-like immunoreactivity in retinoic acid-differentiated neuroblastoma x glioma (NG108-15) cells.J Neurosci Res 1997; 47 (1): 83-9.
73.Bullitt E, Lee CL, Light AR, Willcockson H. The effect of stimulus duration on noxious-stimulus induced c-fos expression in the rodent spinal cord.Brain Res 1992; 580 (1-2): 172-9.
74. Bullitt E. Induction of c-fos-like protein within the lumbar spinal cord and thalamus of the rat following peripheral stimulation. Brain Res 1989;493 (2): 391-7.
75. Abbadie C, Besson JM. c-fos expression in rat lumbar spinal cord during the development of adjuvant-induced arthritis. Neuroscience 1992; 48 (4):985-93.
76. Abbadie C, Lombard MC, Morain F, Besson JM. Fos-like immunoreactivity in the rat superficial dorsal horn induced by formalin injection in the forepaw: effects of dorsal rhizotomies. Brain Res 1992; 578 (1-2): 17-25.
77. Presley RW, MenetreyD, Levine JD, Basbaum AI. Systemic morphine suppresses noxious stimulus-evoked Fos protein-like immunoreactivity in the rat spinal cord. J Neurosci 1990; 10 (1): 323-35.
78.Dolan S, Field LC, Nolan AM. The role of nitric oxide and prostaglandin signaling pathways in spinal nociceptive processing in chronic inflammation. Pain 2000; 86 (3): 311-20.
79.Haley JE, Sullivan AF, Dickenson AH. Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Res 1990; 518 (1-2): 218-26.
80.Herdegen T, Kovary K, Leah J, Bravo R. Specific temporal and spatial distribution of JUN, FOS, and KROX-24 proteins in spinal neurons following noxiouse transsynaptic stimulation. J Comp Neurol 1991; 313 (1): 178-91.
81. Labuz D, Chocyk A, Wedzony K, Toth G, Przewlocka B. Endomorphine-2, deltorphin II and their analogs suppress formalin-induced nociception and c-Fos expression in the rat spinal cord. Life Sci 2003; 73 (4): 403-12.
82.Tolle TR, Castro-Lopes JM, Coimbra A, Zieglgansberger W. Opiates modify induction of c-fos proto-oncogene in the spinal cord of the rat followingnoxious stimulation. Neurosci Lett 1990; 111 (1-2): 46-51.
83．曹君利，曾因明，张励才．NO参与介导吗啡戒断大鼠脊髓神经元敏感化．生理学报2001：53(1)：75-84．
84. Handy RL, Moore PK. A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity. Br J Pharmacol 1998; 123 (6): 1119-26.
85. Ayers NA, Kapas L, Krueger JM. The inhibitory effects of N-omega-nitro-L-arginine methyl ester on nitric oxide synthase activity vary among brain regions in vivo but not in vitro. Neurochem Res 1997; 22 (1): 81-6.
86. Malmberg AB, Yaksh TL. The effect of morphine on formalin-evoked behaviour and spinal release of excitatory amino acids and prostaglandin E2 using microdialysis in conscious rats. Br J Pharmacol 1995; 114 (5): 1069-75.
87. Lawand NB, McNearney T, Westlund KN. Amino acid release into the knee joint: key role in nociception and inflammation. Pain 2000; 86 (1-2): 69-74.
88. Malmberg AB, Yaksh TL. Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: a microdialysis study in unanesthetized rats. J Neurosci 1995; 15(4): 2768-76.
89. Mayer ML, Westbrook GL, Guthrie PB. Voltage-dependent block by Mg2+of NMDA responses in spinal cord neurons. Nature 1984; 309 (5965): 261-3.
90. Headley PM, Grillner S. Excitatory amino acids and synaptic transmission: the evidence for a physiological function. Trends Pharmacol Sci 1990; 11 (5): 205-11.
91. Yaksh TL. Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature 1980; 286 (5769): 155-7.
92. Budd PC, Nicholls DG, McLaughlin M. The target of PKC induced suppression of adenosine inhibition of glutamate release from synaptosomes is downstream of the A1 receptor and G-protein coupling. Biochem Soc Trans 1996; 24 (3): 429S.
93. Sanchez-Prieto J, Budd PC, Herrero I, Vazquez E, Nicholls DG. Presynaptic??receptors and the control of glutamate exocytosis. Trends Neurosci 1996; 19 (6): 235-9.
94. Coderre TJ. Contribution of protein kinase C to central sensitization and persistent pain following tissue injury. Neurosci Lett 1992; 140 (2): 181-4.
95. Wen ZH, Chang YC, Cherng CH, Wang JJ, rao PL, Wong CS. Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats. Brain Res 2004; 995 (2): 253-9.
96. Ferreira SH, Lorenzetti BB. Glutamate spinal retrograde sensitization of primary sensory neurons associated with nociception. Neuropharmacology 1994; 33 (11): 1479-85.
97. Ozawa T, Nakagawa T, Shige K, Minami M, Satoh M. Changes in the expression of glial glutamate transporters in the rat brain accompanied with morphine dependence and naloxone-precipitated withdrawal. Brain Res 2001; 905 (1-2): 254-8.
98. Yrotti O, Peng JB, Dunlop J, Hediger MA. Inhibition of the glutamate transporter EAAC1 expressed in Xenopus oocytes by phorbol esters. Brain Res 2001; 914 (1-2): 196-203.
99. Mao J, Sung B, Ji RR, Elm G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002; 22 (18): 8312-23.
100. Heinzen EL, Pollack GM. The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice. Biochem Pharmacol 2004; 67 (4): 735-41.
101．刘惠芬，周文华，谢小虎，曹君利，顾钧，杨国栋．M受体对吗啡戒断大鼠脊髓和脑干NMDA受体基因表达及中脑导水管周围灰质中谷氨酸释放的调节．生理学报2004：56(1)：95-100．
102. Zhu H, Brodsky M, Gorman AL, and Inturrisi CE Region-specific changes in NMDA receptor mRNA induced by chronic morphine treatment are prevented by the co-administration of the competitive NMDA receptor antagonist LY274614.??Brain Res Mol 8rain Res 2003; 114 (1): 154-62.
103. Leza JC, Lizasoain I, San-Martin-Clark O, Lorenzo P. Morphine-induced changes in cerebral and cerebellar nitric oxide synthase activity. Eur J Pharmacol 1995; 285 (1): 95-8.
104. Elliott K, Minami N, Kolesnikov YA, Pasternak GW, Inturrisi CE. The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. Pain 1994; 56 (1): 69-75.
105. Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001; 81 (1): 299-343.
106．曹君利，刘惠芬，周文华，杨国栋，张励才，曾因明．鞘内注射NOS反义寡核苷酸抑制吗啡戒断大鼠脊髓和脑干NADA1A受体mRNA表达的增加．生理学报2001：53(1)：27-31．
107. Soares-Mota M, Henze I, Mendez-Otero R. Nitric oxide synthase-positive neurons in the rat superior colliculus: colocalization of NOS with NMDAR1 glutamate receptor, GABA, and parvalbumin. J Neurosci Res 2001; 64 (5): 501-7.1.MillanMJ. The induction of pain: an integrative review. Prog Neurobiol 1999;57 (1): 1-164.
2. Dubner R, Bennett GJ. Spinal and trigeminal mechanisms of nociception. Annu Rev Neurosci 1983; 6; 381-418.
3.Sherrington CS. The integrative action of the nervous system. Scribner,New York 1906.
4. Lembech F, Donnerer J. The wide spectrum of function of capsaicin-sensitive nociceptive afferents. In; sicuteri F, Advances in pain research and therapy. Raven Press Ltd, New York 1992; 45-53.
5.Ren K. Primary afferents and inflammatory hyperexcitability. Pain 1996;67 (1): 1-2.
6. Bessou P, Perl ER. Reponse of cutaneous sensory units with unmyelinated fibers to noxious stimuli. J Neurophysiol 1969; 32 (6): 1025-43.
7. Van Hees J. Human C-fiber input during painfull and nonpainful skin stimulation with radiant heat. In:Bonica JJ.Alble-Fessard DG (eds) Advances in pain research and therapy, vol 1. Raven, New York 1976; 35-40.
8. Cervero F. Sensory innervation of the viscera: peripheral basis of visceral pain. Physiol Rev 1994; 74 (1): 95-138.
9. Cervero F. Visceral pain: mechanisms of peripheral and central sensitization.Ann Med 1995; 27 (2): 235-9.
10. Gebhart GF. Visceral nociception: consequences, modulation and the future.Eur J Anaesthesiol 1995; 10: S24-7.
11. Pitcher GM, Henry JL. Cellular mechanisms of hyperalgesia and spontaneous pain in a spinalized rat model of peripheral neuropathy: changes in myelinated afferent inputs implicated. Eur J Neurosci 2000; 12(6): 2006-20.
12. Baumann TK, Simone DA, Shain CN, LaMotte RH. Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol, 1991, 66 (1):??212-27.
13. Ckube MA, Ochoa J, Torebjork HE. Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain 1989; 112 (Pt 3): 621-47.
14. Torebjork HE, Linberg LE, Lamotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 1992; 448: 765-80.
15. Ren K, Williams GM, Ruda MA, Dubner R. Inflammation and hyperalgesia in rats neonatally treated with capsaicin:effects on two classes of nociceptive neurons in the superficial dorsal horn. Pain 1994; 59 (2): 287-300.
16. Herrero JF, de la Rubia PG, Cervero F. Wind-up of spinal cord neurons is influenced by inflammation, spinalization, endogenous opiods and type of stimulation. Soc Neurosci Abstr 1995; 21: 1407.
17. Ma QP , Woolf JC. Noxious stimuli induce an N-methyl-D-aspartate receptor-dependent hypersensitivity of the flexion withdrawal reflexes to touch: implications for the treatment of mechanical allodynia. Pain 1995;61 (3) : 383-90.
18. Neugerbauer VT. NMDA and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat' s knee joint. J Neurophsiology 1993; 44 (4): 1365-77.
19. LaMotte RH, Shain CN, Simone DA, Tsai EF. Neurogenic hyperalgesia: Psychophysiol studies of underlying mechanism. J Neurophsiol 1991; 66 (1):190～211.
20. Woolf CJ. The dorsal horn: state-dependent sensory processing and the generation of pain. In: Wall PD, Mealzack R, ed. Textbook of pain. Edinburgh:Churchill Livingstone 1994; 101.
21. Price DD, Hayes RL, Ruda M, Dubner R. Spatial and temporal transformations of input to spinothalamic tract neurons and their relation to somatic sensations. J Neurophysiol 1978; 41 (4): 933-47.
22.You HJ, Dahl Morch C, Chen J, Arendt-Nielsen L. Simultaneous recordings of wind-up of paired spinal dorsal horn nociceptive neuron and nociceptive??flexion reflex in rats. Brain Res 2003; 960 (1-2): 235-45.
23.Culberson JL, Haines DE, Kimmel DL, Brown PB. Contralateral projection of primary afferent fibers to mammalian spinal cord. Exp Neurol 1979; 64 (1):83-97.
24. SugiuraY, Lee CL, Perl ER. Central projections of identified, unmyelinated (C) afferent fibers innervating mammalian skin. Science 1986; 234(4774):358-61.
25. Biella G, Riva L, Sotgiu ML. Interaction between neurons in different laminae of the dorsal horn of the spinal cord. A correlation study in normal and neuropathic rats. Eur J Neurosci 1997; 9 (5): 1017-25.
26. Coggeshall RE, Carlton SM. Receptor localization in the mammalian dorsal horn and primary afferent neurons. Brain Res Rev 1997; 24 (1): 28-66.
27. Takakusaki K, Kohyama J, Matsuyama K, Mori S. Medullary reticulospinal tract mediating the generalized motor inhibition in cats: parallel inhibitory mechanisms acting on motoneurons and on interneuronal transmission in reflex pathways. Neurosci 2001; 103 (2): 511-27.
28. Bao L, Wang HF, Cai HJ, et al.. Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord. Eur J Neurosci 2002; 16 (2): 175-85.
29. Kawasaki Y, Kohno T, Zhuang ZY, et al. Ionotropic and metabotropic receptors,protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci 2004;24 (38): 8310-21.
30. Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA. Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci 2002; 22 (20): 9086-98.
31. Yang K, Ma WL, Feng YP, Dong YX, Li YQ. Origins of GABA (B) receptor-like immunoreactive terminals in the rat spinal dorsal horn. Brain Res Bull 2002;58 (5): 499-507
32.Hama AT, Fritschy JM, Hammond DL. Differential distribution of (GABA) A receptor subunits on bulbospinal serotonergic and nonserotonergic neurons of the ventromedial medulla of the rat. J Comp Neurol 1997; 384 (3): 337-48.
33.Todd AJ , Spike RC. The localization of classical transmitters and neuropeptides within neurons in laminae I—III of the mammalian spinal dorsal horn. Prog Neurobiol 1993; 41 (5): 609-45.
34.Soares-Mota M, Henze I, Mendez-Otero R. Nitric oxide synthase-positive neurons in the rat superior colliculus: colocalization of NOS with NMDAR1 glutamate receptor, GABA, and parvalbumin. J Neurosci Res. 2001; 64 (5):501-7.
35.Pitcher GM , Henry JL. Nociceptive response to innocuous mechanical stimulation is mediated via myelinated afferents and NK-1 receptor activation in a rat model of neuropathic pain. Exp Neurol 2004; 186 (2):173-97.
36. Valtschanoff JG, Weinberg RJ, Rustioni A. Central release of tracer after noxious stimulation of the skin suggests non-synaptic signaling by unmyelinated fibers. Neurosci 1995; 64 (4): 851-4.
37.Millan MJ, Perrin-Monneyron S. Potentiation of fluoxetine-induced penile erections by combined blockade of 5-HT1A and 5-HT1B receptors. Eur J Pharmacol 1997; 321 (3): R11-3.
38.Kolhekar R, Murphy S , Gebhart GF. Thalamic NMDA receptors modulate inflammation-produced hyperalgesia in the rat. Pain 1997; 71 (1): 31-40.
39.Mayer ML, Westbrook GL. The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 1987; 28 (3): 197-276.
40. Vetter G, Geisslinger G, Tegeder I. Release of glutamate, nitric oxide and prostaglandin E2 and metabolic activity in the spinal cord of rats following peripheral nociceptive stimulation. Pain 2001; 92 (1-2): 213-8.
41.Borszcz GS, Johnson CP, Williams DH. Increases in vocalization and motor reflex thresholds generated by the intrathecal administration of serotonin or norepinephrine. Behav Neurosci 1996; 110 (4): 809-22.
42. Gao K, Mason P. Serotonergic Raphe magnus cells that respond to noxious tail heat are not ON or OFF cells. J Neurophysiol 2000; 84 (4): 1719-25.
43. Antal M, Petko M, Polgar E, Heizmann CW, Storm-Mathisen J. Direct evidence of an extensive GABAergic innervation of the spinal dorsal horn by fibres descending from the rostral ventromedial medulla. Neurosci 1996; 73 (2):509-18.
44. Wang D, Li YQ, Li JL, KanekoT, Nomura S, MizunoN. Gamma-aminobutyric acid-and glycine-immunoreactive neurons postsynaptic to substance P-immunoreactive axon terminals in the superficial layers of the rat medullary dorsal horn. Neurosci Lett 2000; 288 (3): 187-90.
45. Chen YP, Chen SR, Pan HL. Systemic morphine inhibits dorsal horn projection neurons through spinal cholinergic system independent of descending pathways. J Pharmacol Exp Ther 2005; 314 (2): 611-7.
46.Xie JY, Herman DS, Stiller CO, et al. Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. J Neurosci 2005; 25 (2): 409-16.
47. Almeida A, Tjolsen A, Lima D, Coimbra A, Hole K. The medullary dorsal reticular nucleus facilitates acute nociception in the rat. Brain Res Bull 1996;39 (1): 7-15.
48.Bardin L, Jourdan D, Alloui A, Lavarenne J, Eschalier A. Differential influence of two serotonin 5-HT3 receptor antagonists on spinal serotonin-induced analgesia in rats. Brain Res 1997; 765 (2): 267-72.
49.Urban MO, Smith DJ, Gebhart GF. Involvement of spinal cholecystokininB receptors in mediating neurotensin hyperalgesia from the medullary nucleus raphe magnus in the rat. J Pharmacol Exp Ther 1996; 278 (1): 90-6.
50. Abacioglu N, Tunctan B, Akbulut E, Cakici I. Participation of the components of L-arginine/nitric oxide/cGMP cascade by chemically-induced abdominal constriction in the mouse. Life Sci 2000; 67 (10): 1127-37.
51.Okuda K, Sakurada C, Takahashi M, Yamada T, Sakurada T. Characterization of nociceptive responses and spinal releases of nitric oxide metabolitesand glutamate evoked by different concentrations of formalin in rats. Pain 2001; 92 (1-2): 107-15.
52.Azkue JJ, Knopfel T, Kuhn R, Mateos JM, Grandes P. Distribution of the metabotropic glutamate receptor subtype mGluR5 in rat midbrain periaqueductal grey and relationship with ascending spinofugal afferents.Neurosci Lett 1997; 228 (1): 1-4.
53. Eaton SA, Salt TE. Role of N-methyl-D-aspartate and metabotropic glutamate receptors in corticothalamic excitatory postsynaptic potentials in vivo.Neurosci 1996; 73 (1): 1-5.
54.ZouX, Lin Q, Willis WD. Enhanced phosphorylation of NMDA receptor 1 subunits in spinal cord dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. J Neurosci 2000; 20 (18): 6989-97.
55. Popratiloff A, Rustioni A, Weinberg RJ. Heterogeneity of AMPA receptors in the dorsal column nuclei of the rat. Brain Res 1997; 754 (1-2): 333-9.
56. Elena Erro M, Lanciego JL, Gimenez-Amaya JM. Re-examination of the thalamostriatal projections in the rat with retrograde tracers. Neurosci Res 2002;42 (1): 45-55.
57. Li JL, Ding YQ, Shigemoto R, Mizuno N. Distribution of trigeminothalamic and spinothalamic-tract neurons showing substance P receptor-like immunoreactivity in the rat. Brain Res 1996; 719 (1-2): 207-12.
58. Li JL, Mizuno N. Parabrachial nucleus neurons providing axons to both the thalamus and the spinal cord in the rat. Brain Res 1997; 745 (1-2): 321-7.
59. Yasui Y, Yokota S, Ono K, Tsumori T. Projections from the red nucleus to the parvicellular reticular formation and the cervical spinal cord in the rat, with special reference to innervation by branching axons. Brain Res 2001; 923 (1-2): 187-92.
60.Nichols ML, Lopez Y, Ossipov MH, Bian D, Porreca F. Enhancement of the antiallodynic and antinociceptive efficacy of spinal morphine by antisera to dynorphin A (1-13) or MK-801 in a nerve-ligation model of peripheral neuropathy. Pain 1997; 69 (3): 317-22.
61.Brauneis U, Oz M, Peoples RW, Weight FF, Zhang L. Differential sensitivity of recombinant N-methyl-D-aspartate receptor subunits to inhibition by dynorphin. J Pharmacol Exp Ther 1996; 279 (3): 1063-8.
62. PeyronR, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000) . Neurophysiol Clin 2000; 30(5): 263-88.
63. Derbyshire SW, Jones AK, Gyulai F, Clark S, Townsend D, Firestone LL. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 1997; 73 (3): 431-45.
64. Derbyshire SW, Jones AK, Creed F, et al. Cerebral responses to noxious thermal stimulation in chronic low back pain patients and normal controls. Neuroimage 2002; 16 (1): 158-68.
65. Bonham AC, Chen CY. Glutamatergic neural transmission in the nucleus tractus solitarius: N-methyl-D-aspartate receptors. Clin Exp Pharmacol Physiol 2002; 29 (5-6): 497-502.
66.Liaw WJ, Stephens RL Jr, Binns BC, et al. Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 2005; 115 (1-2): 60-70.
67. Peng YB, Wu J, Willis WD, Kenshalo DR. GABA (A) and 5-HT (3) receptors are involved in dorsal root reflexes: possible role in periaqueductal gray descending inhibition. J Neurophysiol 2001; 86 (1): 49-58.
68.Do KQ, Binns KE, Salt TE. Release of the nitric oxide precursor, arginine,from the thalamus upon sensory afferent stimulation, and its effect on thalamic neurons in vivo. Neurosci 1994; 60 (3): 581-6.
69. Terayama R, Guan Y, Dubner R, Ren K. Activity-induced plasticity in brain stem pain modulatory circuitry after inflammation. Neuroreport 2000; 11(9): 1915-9.
70.Guan Y, Terayama R, Dubner R, Ren K. Plasticity in excitatory amino acid receptor-mediated descending pain modulation after inflammation. J Pharmacol Exp Ther 2002; 300 (2): 513-20.
71.Bredt DS and Snyder SH. Isolation of nitric oxide systhase , a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 1990; 87 (2): 682-5.
72. Bredt DS, Glatt CE, Hwang PM, Fotuhi M, Dawson TM, Snyder SH. Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 1991; 7 (4):615-24.
73. Forstermann U, Schmidt HH, Pollock JS, et al. Isoforms of nitric oxide synthase. Characterization and purification from different cell types. Biochem Pharmacol 1991; 42 (10): 1849-57.
74. Solodkin A, Traub RJ, Gebhart GF. Unilateral hindpaw inflammation produces a bilateral increase in NADPH-diaphorase histochemical staining in the rat lumbar spinal cord. Neurosci 1992; 51 (3): 495-9.
75. Fiallos-Estrada CE, Kummer W, Mayer B, Bravo R, Zimmermann M, Herdegen T. Long-lasting increase of nitric oxide synthase immunoreactivity ,NADPH-diaphorase reaction and c-JUN co-expression in rat dorsal root ganglion neurons following sciatic nerve transection. Neurosci Lett 1993;150 (2): 169-73.
76.Herdegen T, Kovary K, Leah J, Bravo R. Specific temporal and spatial distribution of JUN, FOS, and KROX-24 proteins in spinal neurons following noxiouse transsynaptic stimulation. J Comp Neuro 1991; 313 (1): 178-91.
77.Barinaga M. Is nitric oxide the "retrograde messenger"? Science 1991;254 (5036): 1296-7.
78. Bult H, Boeckxstaens GE, Pelckmans PA, Jordaens FH, Van Maercke YM, Herman AG. Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature 1990; 345 (6273): 346-7.
79. McCall T and VallanceP. Nitric oxide take center-stage with newly defined roles, Trendes Pharmacol Sci 1992; 13 (1): 1-6.
80. Kitto KF, Haley JE, Wilcox GL. Involvement of nitric oxide in spinally mediated hyperalgesia in the mouse. Neurosci Lett 1992; 148 (1-2): 1-5.
81. Lin Q, Wu J, Peng YB, Cui M, Willis WD. Inhibition of primate spinothalamictract neurons by spinal glycine and GABA is modulated by guanosine 3', 5'-cyclic monophosphate. J Neurophysiol 1999; 81 (3): 1095-103.
82. Lin Q, Peng YB, Willis WD. Role of GABA receptor subtypes in inhibition of primate spinothalamic tract neurons : difference between spinal and periaqueductal gray inhibition. J Neurophysiol 1996 ; 75 (1): 109-23.
83. Knowles RG, Merrett M, Salter M, MoncadaS. Differential induction of brain,lung and liver nitric oxide synthase by endotoxin in the rat. Biochem J 1990;270 (3): 833-6.
84. Knowles RG, PalaciosM, Palmer RM, MoncadaS, Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci USA 1989;86 (13): 5159-62.
85. Vincent SR, Hope BT. Neurons that say NO. Trends Neurosci 1992; 15 (3):108-13.
86.Pan HL, Chen SR, Eisenach JC. Intrathecal clonidine alleviates allodynia in neuropathic rats: interaction with spinal muscarinic and nicotinic receptors. Anesthesiology 1999; 90 (2): 509-14.
87. Xu Z, Chen SR, Eisenach J, Pan HL. Role of spinal muscarinic and nicotinic receptors in clonidine-induced nitric oxide release in a rat model of neuropathic pain. Brain Res 2000; 861 (2): 390-8.
88.Peunova N , Enikolopov G. Amplification of calcium-induced gene transcription by nitric oxide in neuronal cells. Nature 1993; 364 (6436):450-3.
89.Ciani E, Guidi S, Bartesaghi R, Contestabile A. Nitric oxide regulates cGMP-dependent cAMP-responsive element binding protein phosphorylation and Bcl-2 expression in cerebellar neurons: implication for a survival role of nitric oxide. J Neurochem 2002; 82 (5): 1282-9.
90.Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.Nature 2002; 415 (6873): 793-8.
91.Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science. 1992; 256 (5060): 1217-21.
92.Mori H, Mishina M. Structure and function of the NMDA receptor channel.Neuropharmacology 1995; 34 (10): 1219-37.
93. Mayer ML, Westbrook GL, Guthrie PB. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurons. Nature 1984; 309 (5965): 261-3.
94.Mayer ML, Westbrook GL. Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones.J Physiol 1987; 394: 501-27.
95.East SJ and Garthwaite J, NMDA receptor activition in rat hippocampus induceds cyclic GMP formation through the L-arginine-nitric oxide pathway.Neurosci Lett 1991; 123 (1): 17-9.
96. Tao YX, Johns RA, Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw. Neurosc 2002; 112 (2): 439-46.
97. BredtDS, Snyder SH, Nitric oxide, a novel neuronal messenger. Neuron 1992;8 (1): 3-11.
98. Vikman KS, Duggan AW, Siddall PJ. Increased ability to induce long-term potentiation of spinal dorsal horn neurones in monoarthritic rats. Brain Res 2003; 990 (1-2): 51-7.
99.Pedersen LM, Lien GF, Bollerud I, Gjerstad J. Induction of long-term potentiation in single nociceptive dorsal horn neurons is blocked by the CaMKII inhibitor AIP. Brain Res 2005; 1041 (1): 66-71.
100. Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003; 26 (12):696-705.
101. Malenka RC, Nicoll RA. Learning and memory. Never fear, LTP is hear. Nature 1997; 390 (6660): 552-3.
102. Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989; 63 (2): 139-46.
103. Woolf CJ, Shortland P, Coggeshall RE. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 1992:355 (6355): 75-8.
104. Dubner R, Ruda MA, Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends Neurosci 1992; 15 (3): 96-103.
105. Meller ST, Dykstra C, Gebhart GF. Production of endogenous nitric oxide and activation of soluble guanylate cyclase are required for N-methyl-D-aspartate-produced facilitation of the nociceptive tail-flick reflex. Eur J Pharmacol 1992; 214 (1): 93-6.
106. Yamamoto T, Yaksh TL. Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve. Excitatory amino acid antagonists. Pain 1992; 49 (1): 121-8.
107. Collingridge GL, Blake JF, Brown MW, Bashir ZI, Ryan E. Involvement of excitatory amino acid receptors in long-term potentiation in the Schaffer collateral-commissural pathway of rat hippocampal slices. Can T Physiol Pharmacol 1991; 69 (7): 1084-90.
108. Headley PM, Grillner S. Excitatory amino acids and synaptic transmission: the evidence for a physiological function. Trends Pharmacol Sci 1990; 11 (5): 205-11.
109．钟敏．疼痛中枢敏感化的分子机制．《国外医学》麻醉学与复苏分册2000；21(3)：148-51．
110. Davidson EM, Coggeshall RE, Carlton SM. Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviors in the rat formalin test. Neuroreport 1997; 8 (4): 941-6.
111. Lawand NB, McNearney T, Westlund KN. Amino acid release into the knee joint: key role in nociception and inflammation. Pain 2000; 86 (1-2): 69-74.
112. Soliman AC, Yu JS, Coderre TJ. mGlu and NMDA receptor contributions to capsaicin-induced thermal and mechanical hypersensitivity. Neuropharmacology 2005; 48 (3): 325-32.113.Ro JY, Nies M, Zhang Y. The role of peripheral N-methyl-D-aspartate receptors in muscle hyperalgesia. Neuroreport 2005; 16 (5): 485-9.
114. Kawamata T, Omote K. Activation of spinal N-methyl-D-aspartate receptors stimulates a nitric oxide/cyclic guanosine 3, 5-monophosphate/glutamate release cascade in nociceptive signaling. Anesthesiology 1999; 91 (5):1415-24.
115. North RA, Williams JT, Surprenant A, Christie MJ. Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. Proc Natl Acad Sci USA 1987; 84 (15): 5487-91.
116.Connor M, Vaughan CW, Chieng B, Christie MJ. Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro. Br J Pharmacol 1996; 119 (8): 1614-8.
117. Rusin KI, Moises HC. Mu-opioid and GABA (B) receptors modulate different types of Ca2+ currents in rat nodose ganglion neurons. Neurosci 1998;85 (3): 939-56.
118. Williams JT, Christie MJ, Manzoni 0. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001; 81 (1): 299-343. Review.
119. Kieffer BL. Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides. Cell Mol Neurobiol 1995; 15 (6): 615-35.
120.孙国勤,徐惠芳.阿片受体亚型研究进展.生命的化学 2000; 20 (3): 106-9.
121.Wang HQ, Kampine JP, Tseng LF. Antisense oligodeoxynucleotide to a delta-opioid receptor messenger RNA selectively blocks the antinociception induced by intracerebroventricularly administered delta-, but not mu-, epsilon- or kappa-opioid receptor agonists in the mouse.Neurosci 1996; 75 (2): 445-52.
122. Simonin F, Valverde 0, Smadja C, et al. Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain,impairs pharmacological actions of the selective kappa-agonist U-50, 488H and attenuates morphine withdrawal. EMBO J 1998 16; 17 (4):886-97.
123. Kress M, Guthmann C, Averbeck B, Reeh PW. Calcitonin gene-related peptide and prostaglandin E2 but not substance P release induced by antidromic nerve stimulation from rat skin in vitro. Neurosci 1999; 89 (1): 303-10.
124. BalletS, Mauborgne A, Benoliel JJ, et al. Olyarthritis-associated changes in the opioid control of spinal CGRP release in the rat. Brain Res 1998;796 (1-2): 198-208.
125.Georges F, Stinus L, Bloch B, Le Moine C. Chronic morphine exposure and spontaneous withdrawal are associated with modifications of dopamine receptor and neuropeptide gene expression in the rat striatum. Eur J Neurosci 1999; 11 (2): 481-90.
126. Shippenberg TS, Rea W. Sensitization to the behavioral effects of cocaine:modulation by dynorphin and kappa-opioid receptor agonists. Pharmacol Biochem Behav 1997; 57 (3): 449-55.
127.King MA, Bradshaw S, Chang AH, Pintar JE, Pasternak GW. Potentiation of opioid analgesia in dopamine2 receptor knock-out mice: evidence for a tonically active anti-opioid system. J Neurosci 2001; 21 (19): 7788-92.
128. Dalman FC, 0' Malley KL. kappa-Opioid tolerance and dependence in cultures of dopaminergic midbrain neurons. J Neurosci 1999; 19 (14): 5750-7.
129.Schuman EM, Madison DV. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 1991; 254 (5037): 1503-6
130. Majeed NH, Przewlocka B, Machelska H, Przewlocki R. Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice. Neuropharmacology 1994; 33 (2): 189-92.
131. Yamaguchi H, Naito H. Antinociceptive synergistic interaction between morphine and n-omega nitro-L-arginine methyl ester on thermal nociceptive tests in the rats. Can J Anaesth 1996; 43 (9): 975-81.
132.Benamar K, Xin L, Geller EB, Adler MW. Modulation of morphine analgesia by a nitric oxide synthase inhibitor microinjected into the periaqueductal gray in rats. Analgesia 2002; 6 (1-3): 7-10.
133. Przewlocki R, Machelska H, Przewlocka B. Inhibation of nitric oxide synthaseenhances morphine antinociception in the rat spinal cord. Life Sci 1993;53 (1): PL1-5.
134.Babey AM, Kolesnikov Y, Cheng J, Inturrisi CE, Trifilletti RR, Pasternak GW. Nitric oxide and opioid tolerance. Neuropharmacology 1994; 33 (11):1463-70.
135. Zek M, Uresin Y, Gungor M. Comparison of the effects of specific and nonspecific inhibition of nitric oxide synthase on morphine analgesia, tolerance and dependence in mice. Life Sci 2003; 72 (17): 1943-51.
136. Rauhala P , Idanpaan-Heikkila JJ , Tuominen RK , Mannisto PT. N-nitro-L-arginine attenuates development of tolerance to antinociceptive but not to hormonal effects of morphine. Eur J Pharmacol. 1994; 259 (1):57-64.
137. Pataki I, Telegdy G. Further evidence that nitric oxide modifies acute and chronic morphine actions in mice. Eur J Pharmacol 1998; 357 (2-3): 157-62.
138. Bhargava HN, BianJT, N (G) -nitro-L-arginine reverses L-arginine induced changes in morphine antinociception and distribution of morphine in brain regions and spinal cord of the mouse. Brain Research 1997; 749 (2): 351-3.
139. Kolesnikov YA, Pick CG, Pasternak GW. NG-nitro-L-arginine prevents morphine tolerance. Eur J Pharmacol 1992; 221 (2-3): 399-400.
140. Kolesnikov YA,, Pick CG, CiszewskaG, Pasternak GW. Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor.Proc Natl Acad Sci U S A 1993; 90 (11): 5162-6.
141. Xu JY, Tseng LF. Nitric oxide/cyclic guanosine monophosphate system in the spinal cord differentially modulates intracerebroventricularly administered morphine-and beta-endorphin-induced antinociception in the mouse. J Pharmacol Exp Ther 1995; 274 (1): 8-16.
142.Pelligrino DA Laurito CE Vade B Timothy R. Nitric Oxide Synthase Inhibition Modulates the Ventilatory Depressant and Antinociceptive Actions of Fourth Ventricular Infusions of Morphine in the Awake Dog. Anesthesiology. 1996; 85 (6): 1367-77.
143. Li XQ, Clark JD, Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. Brain research Molecular Brain Research 2001; 95 (1-2): 96-102.
144. Dunbar S, Yaksh TL. Effect of spinal infusion of L-NAME, a nitric oxide synthase inhibitor, on spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Neurosci Lett 1996; 207 (1): 33-6.
145. Heinzen EL, Pollack GM. The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice. Biochem Pharmacol 2004; 67 (4): 735-41.
146. Wong CS, Hsu MM, Chou YY, Tao PL, Tung CS. Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord. Br J Anaesth 2000; 85 (4): 587-91.
147. Cuellar B, Fernandez AP, Lizasoain I, Moro MA, Lorenzo P, Bentura ML, Rodrigo J, Leza JC. Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal. Psychopharmacology 2000; 148 (1): 66-73.
148．曹君利，曾因明，张励才．NO参与介导吗啡戒断大鼠脊髓神经元敏感化．生理学报2001：53(1)：75-84．
149. Machelska H, Ziolkowska B, Mika J, Przewlocka B, Przewlocki R. Chronic morphine increases biosynthesis of nitric oxide synthase in the rat spinal cord. Neuroreport 1997; 8 (12): 2743-7.
150. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991; 251 (4989): 85-7.
151. Wen ZH, Chang YC, Cherng CH, Wang JJ, Tao PL, Wong CS. Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats. Brain Res 2004; 995 (2): 253-9.
152. Beczkowska IW, Gracy KN, Pickel VM, Inturrisi CE. Detection of delta opioid receptor and N-methyl-D-aspartate receptor-like immunoreactivity in retinoic acid-differentiated neuroblastoma x glioma (NG108-15) cells. J Neurosci Res 1997; 47 (1): 83-9.153. Dunbar SA, Pulai IJ. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat. J Pharmacol Exp Ther 1998; 284 (2): 678-86.
154. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002; 22 (18): 8312-23.
155. Koyuncuoglu H, Nurten A, Yamanturk P, Nurten R. The importance of the number of NMDA receptors in the development of supersensitivity or tolerance to and dependence on morphine. Pharmacol Res 1999; 39 (4): 311-9.
156. Watanabe C, Okuda K, Sakurada C, Ando R, Sakurada T, Sakurada S. Evidence that nitric oxide-glutamate cascade modulates spinal antinociceptive effect of morphine: a behavioural and microdialysis study in rats. Brain Res 2003; 990 (1-2): 77-86.
157. Liang DY, Clark JD. Modulation of the NO/CO-cGMP signaling cascade during chronic morphine exposure in mice. Neurosci Lett 2004; 365 (1): 73-7.
158. Machelska H, Labuz D, Przewlocki R, Przewlocka B. Inhibition of nitric oxide synthase enhances antinociception mediated by mu, delta and kappa opioid receptors in acute and prolonged pain in the rat spinal cord. J Pharmacol Exp Ther 1997; 282 (2): 977-84.
159. Bhargava HN. Diversity of agents that modify opioid tolerance, physical dependence , abstinence syndrome , and self-administrative behavior. Pharmacol Rev 1994; 46 (3): 293-324.
160. Chapman V, Dickenson AH. The combination of NMDA antagonism and morphine produces profound antinociception in the rat dorsal horn. Brain Res 1992;573 (2): 321-3.
161.Coderre TJ. Contribution of protein kinase C to central sensitization and persistent pain following tissue injury. Neurosci Lett 1992; 140 (2):181-4.
162.Budd DC, Nicholls DG, McLaughlin M. The target of PKC induced suppression of adenosine inhibition of glutamate release from synaptosomes isdownstream of the Al receptor and G-protein coupling. Biochem Soc Trans 1996; 24 (3): 429S.
163. Lopez-Bayghen E, Ortega A. Glutamate-dependent transcriptional regulation of GLAST: role of PKC. J Neurochem 2004; 91 (1): 200-9.