中脑导水管周围灰质P2X3受体在电针镇痛中的作用

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英文题名：Role of Midbrain Periaqueductal Gray P2X3 Receptors in Electroacupuncture-mediated Endogenous Pain Modulatory Systems 作者：肖智 论文级别：博士 学科专业名称：神经生物学 中文关键词：中脑导水管周围灰质 ; 神经痛 ; P2X3受体 ; 电针 ; 内源性镇痛系统 英文关键词：midbrain periaqueductal gray ; neuropathic pain ; P2X3 receptor ; electroacupuncture ; endogenous pain modulatory system 学位年度：2010 导师：阮怀珍 学科代码：071006 学位授予单位：第三军医大学 论文提交日期：2010-05-01

摘要

疼痛对人类健康危害极大,因此对疼痛机制的探索一直是临床医学和神经科学研究的热点和难点。慢性神经痛继发于外周或中枢神经损伤,表现有自发痛(spontaneous pain),痛觉过敏(hyperalgesia)以及触诱发痛(allodynia)等。细胞外的三磷酸腺苷(adenosine 5’-triphosphate,ATP)通过与细胞膜上嘌呤受体(purinoceptors)结合,促进疼痛在外周和中枢的传递,其中P2X3受体亚型是嘌呤受体中一个主要传递疼痛信息的受体。中脑导水管周围灰质(midbrain periaqueductal gray,PAG)在疼痛信息传递中处于承上启下的关键部位,是机体内源性疼痛调制系统(endogenous pain modulatory system)的一个重要组成部分,高位中枢神经系统对疼痛信息的调制往往都通过对PAG功能的调节而实现。在东方国家,电针(electroacupuncture, EA)广泛运用于慢性疼痛的临床治疗已有2000多年历史,疗效可靠,但是一直以来对电针镇痛机理尚不明确,在一定程度上阻碍了电针治疗的临床运用和推广。
     目的:(1)观察Sprague-Dawley(SD)大鼠在外周神经慢性结扎性损伤(chronic constriction injury,CCI)手术所引发慢性神经痛前后热痛阈、机械痛阈的变化和中脑导水管周围灰质外侧部(lateral midbrain periaqueductal gray,lPAG)中P2X3受体表达变化。(2)通过在慢性神经痛大鼠(以下称:CCI大鼠) lPAG微量注射P2X3受体的激动剂和特异性阻断剂,观察CCI大鼠热痛阈和机械痛阈的改变。(3)对CCI大鼠进行多次穴位电针治疗,观察电针治疗前后,CCI大鼠热痛阈和机械痛阈的改变以及lPAG中P2X3受体表达变化,探讨lPAG中P2X3受体表达与电针镇痛的关系,为临床电针治疗慢性神经痛提供新的理论依据。
     方法: (1)建立SD大鼠慢性右侧坐骨神经结扎性损伤模型,通过辐射热实验(radiant heat test)和von Frey纤维丝实验(von Frey filaments test)检测大鼠在神经损伤前后,建模侧后肢热痛阈(thermal withdrawal latency,TWL)和机械痛阈(mechanical withdrawal threshold,MWT)的变化,通过免疫组织化学技术观察lPAG中P2X3受体表达的变化以及通过免疫印迹技术观察lPAG中P2X3蛋白水平变化; (2)通过对CCI大鼠中脑lPAG微量注射P2X3受体的特异性阻断剂A-317491阻断lPAG中P2X3受体功能后,在lPAG微量注射ATP的类似物α,β-亚甲基ATP (α,β-methylene-ATP,α,β-meATP),观察CCI大鼠热痛阈和机械痛阈变化规律;运用脑片全细胞膜片钳技术,观察乳鼠lPAG神经元的α,β-meATP诱发放电和A-317491对α,β-meATP诱发放电的影响; (3)在CCI大鼠建模侧“足三里”和“三阴交”穴给予多次电针刺激,观察电针治疗前后大鼠热痛阈和机械痛阈以及lPAG中P2X3受体表达变化; (4)用针对P2X3基因的反义寡聚核苷酸(oligodeoxynucleotide,ODN)脑内微量注射降低lPAG中P2X3 mRNA表达后,观察对“足三里”穴位电针治疗镇痛作用的影响,以探讨电针治疗和lPAG中P2X3受体表达的关系。
     结果:(1)通过对SD大鼠疏松结扎右侧坐骨神经后成功复制出慢性神经痛动物模型,建模成功大鼠的热痛阈和机械痛阈均下降,CCI术后第14天热痛阈和机械痛阈下降至最低值,14天后热痛阈和机械痛阈均有小幅缓慢上升但与正常大鼠热痛阈和机械痛阈比较差异仍有统计学意义。(2)CCI大鼠中脑PAG中P2X3受体阳性表达与正常大鼠以及假手术大鼠比较有轻度上调,主要阳性表达部位在lPAG,同时lPAG中P2X3受体蛋白水平与正常大鼠和假手术大鼠比较也有轻度升高。(3)在lPAG微量注射ATP类似物α,β-meATP后,与注射前比较,CCI大鼠热痛阈和机械痛阈值有明显升高;当用P2X3受体的特异性阻断剂A-317491在lPAG微量注射进行预处理后,α,β-meATP的痛阈升高效果明显减弱,热痛阈和机械痛阈值升高幅度减少,有统计学意义。(4)α,β-meATP可使乳鼠lPAG神经元放电频率增加, P2X3受体特异性阻断剂A-317491可抑制此作用;(5)在CCI大鼠“足三里”和“三阴交”穴位给予多次电针刺激后,伴随P2X3受体在CCI大鼠lPAG表达上调,CCI大鼠痛阈明显升高;相反,对CCI大鼠进行“非穴位”电针,P2X3受体在lPAG表达无明显变化,CCI大鼠痛阈改变无统计学意义;(6)当用针对P2X3基因的反义寡聚核苷酸lPAG微量注射降低P2X3受体在lPAG中表达后,“足三里”穴位电针对CCI大鼠的镇痛效果明显下降。
     结论:(1)外周神经(坐骨神经)损伤可导致SD大鼠热痛阈和机械痛阈值下降, CCI大鼠lPAG的P2X3阳性表达上升;(2)lPAG微量注射α,β-meATP可引起CCI大鼠热痛阈和机械痛阈值的显著性升高,此作用可因微量注射P2X3受体的特异性阻断剂A-317491预处理而减弱;同时A-317491对lPAG神经元α,β-meATP诱发电流有抑制作用。(3)对CCI大鼠“足三里”穴位给予7次电针刺激,可引起CCI大鼠热痛阈和机械痛阈值的升高以及P2X3受体在lPAG表达的升高;对CCI大鼠“非穴位”进行7次电针,不能引起痛阈升高和P2X3受体在lPAG表达变化;(4)在lPAG多次微量注射针对P2X3基因的反义寡聚核苷酸后明显减弱“足三里”穴位电针对CCI大鼠的镇痛作用。
     综上所述,lPAG中的P2X3受体在脊髓上疼痛调节中起抑制性作用;“足三里”穴位电针刺激通过上调lPAG中P2X3受体表达加强机体内源性镇痛系统作用,缓解CCI大鼠神经痛症状。lPAG中P2X3受体介入了电针镇痛的脊髓上调节机制。
The study on pain mechanisms is always a hot topic in clinic and neuroscience research fields. Neuropathic pain is known as a notorious devastating consequence of central or peripheral nerve injure which is characterized by a combination of spontaneous pain, hyperalgesia and allodynia. Increasing evidence has revealed that the extracellular ATP facilitates pain transmission at peripheral and spinal sites via the P2X receptors and the P2X3 subtype is an important candidate for this effect. Electroacupuncture (EA) has been clinically utilized to manage chronic pain for thousands years in Eastern countries but the mechanisms underlying EA analgesia are still uncertain.
     Objective to⑴study the function of P2X3 receptors in the lateral midbrain periaqueductal gray (lPAG); the relationship between P2X3 receptor expression and neuropathic pain induced by a chronic constriction injure of the right sciatic nerve on Sprague-Dawley(SD) rats. By immunohistochemistry and Western blotting, we observe the P2X3 receptor protein level and expression location in the lPAG and further explore the effect of pretreatment with A-317491, a novel potent and selective antagonist of P2X3 and P2X2/3 receptors, on the analgesic effect of lPAG microinjection of alpha,beta-methylene ATP(α,β-meATP).⑵investigate whether repetitive administration of electroacupuncture (EA) on‘zusanli’and‘sanyinjiao’acupoints could reduce thermal and mechanical hyperalgesia in a rat neuropathic pain model and to explore the relationship between the antinociceptive effect of EA treatment and the expression of P2X3 receptor in the lPAG.
     Methods: The experiment was composed by four series:Series 1. Changes of pain thresholds of SD rats after establishment of rat CCI (chronic constriction injury) model. Study the expression changes of P2X3 receptor in the lPAG by immunohistochemical and immunoblotting analysis. Series 2. Observation of effect of pretreatment with A-317491 on the analgesic effect of lPAG microinjection ofα,β-meATP and the effect of A-317491 onα,β-meATP-induced current of the neonatal rat lPAG neurons. Series 3. Influence of EA treatments on the pain thresholds and investigation of change of P2X3 receptor expression in the lPAG posterior to EA or sham-EA treatment and explore the acupoint specificity of EA treatment on CCI rat either. Series 4. Analgesic effect changes of EA treatments in response to lPAG microinjection of P2X3 antisense ODN.
     Results:
     Part one
     ⑴The inclined-plane test was used in all experimental rats before algesimetry test to study whether CCI operation, drugs or ODNs microinjection and EA treatment exerted certain adverse effects on rats motor function and proprioception, there was no significant difference on the average maximum angle among all experimental groups.
     ⑵The thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) were measured before CCI operation on the right sciatic nerve and at days 2,4,7,10,12,14,18 and 21 respectively after CCI operation. In CCI group, the hind-paw TWL and MWT were decreased gradually and down to the lowest point on day 14 after CCI operation. In the normal and sham-CCI groups, from day 4 to day 21 after CCI operation, the values of TWL and MWT were quite stable.
     ⑶Immunoblots from lPAG homogenates showed an immunopositive band of P2X3 receptors with molecular weight around 55 kDa both in normal, sham-CCI and CCI groups. There was no significant difference between normal and sham-CCI groups. In CCI group, sciatic nerve ligation caused an increase of P2X3 protein level in the lPAG.
     ⑷In CCI groups, P2X3 receptor-specific immunoreactivity was mildly higher and a little more extensive compared with normal group or sham-CCI group at day 14 after CCI operation.
     Part two
     ⑴Rats were randomly divided into two groups, the rats received intra-lPAG injection with sterile saline (0.3μl) or A-317491 (1.5nmol/0.3μl) once daily for 5 consecutive days. After pre-treatment, TWL and MWT showed no significant difference between above two groups. Microinjection of A-317491 alone cause no long-term effects on pain thresholds of CCI rats .
     ⑵The saline and A-317491 group were then divided into two subgroups before microinjection with PBS orα,β-meATP. lPAG microinjection with vehicle (0.3μl PBS) induced no change of the thermal or mechanical nociceptive threshold. In saline group, lPAG microinjection ofα,β-meATP (30 nmol/0.3μl) significantly elevated nociceptive thresholds compared with beforeα,β-meATP microinjection. The antinociceptive effect ofα,β-meATP was attenuated significantly by A-317491 pretreatment.
     ⑶Whole cell voltage-clamp recording was performed on neonatal rat brain slices to obtain the currents of the lPAG neurons. Our data show that A-317491 attenuated the frequency of theα,β-meATP-induced current in lPAG neurons.
     Part three
     ⑴Multiple EA treatments had no significant effect on TWL and MWT values of rats in normal plus EA group. On the contrary, multiple EA treatments significantly increased TWL and MWT values of rats in CCI plus EA group.
     ⑵The P2X3 receptor protein level in lPAG was detected after multiple EA treatments, which reached a statistically significant high level in CCI plus EA group but not in normal plus EA group.
     ⑶The pain thresholds of CCI rats were elevated after multiple sham-EA treatments but still remained lower than rats in CCI plus EA group.
     ⑷NA(non-acupoint)-EA treatments had no significant effect on pain thresholds and the P2X3 receptor protein level in the lPAG of CCI plus NA-EA group rats was not changed after NA-EA treatments.
     Part four
     ⑴TWL and MWT were both increased after 7 times of EA treatment in the antisense ODN or mismatch ODN group rats compared with CCI rats without EA treatment.
     ⑵The antinociceptive effect of EA treatment was attenuated significantly by P2X3 antisense ODN intra-lPAG injection.
     Conclusion:
     The expression change of P2X3 receptor in the lPAG and the elevated pain thresholds after intra-lPAG injection ofα,β-meATP indicate that P2X3 receptors in the lPAG play an inhibitory role in the pain modulatory and thus may be a central target for analgesics. EA produces a long lasting analgesic effect on neuropathic pain and increases expression of P2X3 receptors in the lPAG. The present study for the first time addressed the involvement of purinergic signaling system in EA analgesia on neuropathic pain in rat CCI model, as could deepen our understanding of the mechanism of EA analgesia and provide a rational basis for enhancing EA analgesic effect by potentiating the function of purinergic signaling system at supraspinal level.

引文

1. Scholz, J. and C.J. Woolf, Can we conquer pain? Nat Neurosci, 2002. 5 Suppl: p. 1062-7.
    2. Woolf, C.J. and R.J. Mannion, Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet, 1999. 353(9168): p. 1959-64.
    3. Zimmermann, M., Pathobiology of neuropathic pain. Eur J Pharmacol, 2001. 429(1-3): p. 23-37.
    4. Kim, S.H. and J.M. Chung, An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain, 1992. 50(3): p. 355-63.
    5. Dong, Z.Q., et al., Down-regulation of GFRalpha-1 expression by antisense oligodeoxynucleotide attenuates electroacupuncture analgesia on heat hyperalgesia in a rat model of neuropathic pain. Brain Res Bull, 2006. 69(1): p. 30-6.
    6. Palla, S., Meeting review: Pain in Europe: Third Congress of the European Federation of IASP Chapters. Nice, September 26-29, 2000. J Orofac Pain, 2001. 15(2): p. 174-6.
    7. Wilson, M., Overcoming the challenges of neuropathic pain. Nurs Stand, 2002. 16(33): p. 47-53; quiz 54-5.
    8. Bennett, G.J. and Y.K. Xie, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, 1988. 33(1): p. 87-107.
    9. Holton, P., The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol, 1959. 145(3): p. 494-504.
    10. Burnstock, G., The past, present and future of purine nucleotides as signalling molecules. Neuropharmacology, 1997. 36(9): p. 1127-39.
    11. Cook, S.P. and E.W. McCleskey, Cell damage excites nociceptors through release of cytosolic ATP. Pain, 2002. 95(1-2): p. 41-7.
    12. Honore, P., et al., Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain, 2002. 99(1-2): p. 11-9.
    13. Inoue, K., [ATP receptors in the central nervous system]. Nippon Yakurigaku Zasshi, 1997. 110(4): p. 173-82.
    14. Gu, J.G. and A.B. MacDermott, Activation of ATP P2X receptors elicits glutamaterelease from sensory neuron synapses. Nature, 1997. 389(6652): p. 749-53.
    15. Dorn, G., et al., siRNA relieves chronic neuropathic pain. Nucleic Acids Res, 2004. 32(5): p. e49.
    16. Worthington, R.A., et al., Identification and localisation of ATP P2X receptors in rat midbrain. Electrophoresis, 1999. 20(10): p. 2077-80.
    17. Zimmermann, M., Ethical guidelines for investigations of experimental pain in conscious animals. Pain, 1983. 16(2): p. 109-10.
    18. Tanck, E.N., et al., Effects of age and size on development of allodynia in a chronic pain model produced by sciatic nerve ligation in rats. Pain, 1992. 51(3): p. 313-6.
    19. Rivlin, A.S. and C.H. Tator, Objective clinical assessment of motor function after experimental spinal cord injury in the rat. J Neurosurg, 1977. 47(4): p. 577-81.
    20. Hargreaves, K., et al., A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain, 1988. 32(1): p. 77-88.
    21. Chaplan, S.R., et al., Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods, 1994. 53(1): p. 55-63.
    22. Van Nassauw, L., et al., Role of reactive nitrogen species in neuronal cell damage during intestinal schistosomiasis. Cell Tissue Res, 2001. 303(3): p. 329-36.
    23. Tal, M. and E. Eliav, Abnormal discharge originates at the site of nerve injury in experimental constriction neuropathy (CCI) in the rat. Pain, 1996. 64(3): p. 511-8.
    24. Wall, P.D. and M. Devor, Sensory afferent impulses originate from dorsal root ganglia as well as from the periphery in normal and nerve injured rats. Pain, 1983. 17(4): p. 321-39.
    25. Sheen, K. and J.M. Chung, Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model. Brain Res, 1993. 610(1): p. 62-8.
    26. Yoon, Y.W., H.S. Na, and J.M. Chung, Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain, 1996. 64(1): p. 27-36.
    27. Bendszus, M. and G. Stoll, Caught in the act: in vivo mapping of macrophage infiltration in nerve injury by magnetic resonance imaging. J Neurosci, 2003. 23(34): p. 10892-6.
    28. Colburn, R.W., A.J. Rickman, and J.A. DeLeo, The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol, 1999. 157(2): p. 289-304.
    29. Moalem, G., K. Xu, and L. Yu, T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience, 2004. 129(3): p. 767-77.
    30.刘晓红,神经病理性痛大鼠背根神经节P2X_3受体表达及电生理学特性的改变.第三军医大学学报, 2008. 30(4): p. 288-292.
    31. Huang, C., et al., Attenuation of mechanical but not thermal hyperalgesia by electroacupuncture with the involvement of opioids in rat model of chronic inflammatory pain. Brain Res Bull, 2004. 63(2): p. 99-103.
    32. Chen, Z.P., A. Levy, and S.L. Lightman, Nucleotides as extracellular signalling molecules. J Neuroendocrinol, 1995. 7(2): p. 83-96.
    33. Fredholm, B.B., Purinoceptors in the nervous system. Pharmacol Toxicol, 1995. 76(4): p. 228-39.
    34. Illes, P. and J.A. Ribeiro, Neuronal P2 receptors of the central nervous system. Curr Top Med Chem, 2004. 4(8): p. 831-8.
    35. Burnstock, G., Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev, 2007. 87(2): p. 659-797.
    36. Burnstock, G., Historical review: ATP as a neurotransmitter. Trends Pharmacol Sci, 2006. 27(3): p. 166-76.
    37. Burnstock, G., Purinergic P2 receptors as targets for novel analgesics. Pharmacol Ther, 2006. 110(3): p. 433-54.
    38. Chen, C.C., et al., A P2X purinoceptor expressed by a subset of sensory neurons. Nature, 1995. 377(6548): p. 428-31.
    39. Collo, G., et al., Cloning OF P2X5 and P2X6 receptors and the distribution and properties of an extended family of ATP-gated ion channels. J Neurosci, 1996. 16(8): p. 2495-507.
    40. Close, L.N., et al., Purinergic receptor immunoreactivity in the rostral ventromedial medulla. Neuroscience, 2009. 158(2): p. 915-21.
    41. Lewis, C., et al., Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature, 1995. 377(6548): p. 432-5.
    42. Burnstock, G., A unifying purinergic hypothesis for the initiation of pain. Lancet, 1996. 347(9015): p. 1604-5.
    43. Barclay, J., et al., Functional downregulation of P2X3 receptor subunit in rat sensoryneurons reveals a significant role in chronic neuropathic and inflammatory pain. J Neurosci, 2002. 22(18): p. 8139-47.
    44. Chen, Y., et al., Mechanisms underlying enhanced P2X receptor-mediated responses in the neuropathic pain state. Pain, 2005. 119(1-3): p. 38-48.
    45. Xiang, Z., et al., Functional up-regulation of P2X 3 receptors in the chronically compressed dorsal root ganglion. Pain, 2008. 140(1): p. 23-34.
    46. Mo, G., et al., Subtype-specific regulation of P2X3 and P2X2/3 receptors by phosphoinositides in peripheral nociceptors. Mol Pain, 2009. 5: p. 47.
    47. Novakovic, S.D., et al., Immunocytochemical localization of P2X3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. Pain, 1999. 80(1-2): p. 273-82.
    48. Liu, R.P. and B.L. Hamilton, Neurons of the periaqueductal gray matter as revealed by Golgi study. J Comp Neurol, 1980. 189(2): p. 403-18.
    49. Beitz, A.J., The midbrain periaqueductal gray in the rat. I. Nuclear volume, cell number, density, orientation, and regional subdivisions. J Comp Neurol, 1985. 237(4): p. 445-59.
    50. Behbehani, M.M., Functional characteristics of the midbrain periaqueductal gray. Prog Neurobiol, 1995. 46(6): p. 575-605.
    51. Craig, A.D., Distribution of brainstem projections from spinal lamina I neurons in the cat and the monkey. J Comp Neurol, 1995. 361(2): p. 225-48.
    52. Keay, K.A., et al., Spinal afferents to functionally distinct periaqueductal gray columns in the rat: an anterograde and retrograde tracing study. J Comp Neurol, 1997. 385(2): p. 207-29.
    53. Wiberg, M. and A. Blomqvist, The spinomesencephalic tract in the cat: its cells of origin and termination pattern as demonstrated by the intraaxonal transport method. Brain Res, 1984. 291(1): p. 1-18.
    54. Hudson, P.M. and B.M. Lumb, Neurones in the midbrain periaqueductal grey send collateral projections to nucleus raphe magnus and the rostral ventrolateral medulla in the rat. Brain Res, 1996. 733(1): p. 138-41.
    55. Odeh, F. and M. Antal, The projections of the midbrain periaqueductal grey to the pons and medulla oblongata in rats. Eur J Neurosci, 2001. 14(8): p. 1275-86.
    56. McGaraughty, S., et al., Capsaicin infused into the PAG affects rat tail flick responses to noxious heat and alters neuronal firing in the RVM. J Neurophysiol, 2003. 90(4): p. 2702-10.
    57. Verberne, A.J. and P.G. Guyenet, Midbrain central gray: influence on medullary sympathoexcitatory neurons and the baroreflex in rats. Am J Physiol, 1992. 263(1 Pt 2): p. R24-33.
    58. Xing, J., J. Lu, and J. Li, Purinergic P2X receptors presynaptically increase glutamatergic synaptic transmission in dorsolateral periaqueductal gray. Brain Res, 2008. 1208: p. 46-55.
    59. Millan, M.J., Descending control of pain. Prog Neurobiol, 2002. 66(6): p. 355-474.
    60. Zhuo, M. and G.F. Gebhart, Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat. J Neurophysiol, 1997. 78(2): p. 746-58.
    61. Milligan, E.D., et al., Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci, 2003. 23(3): p. 1026-40.
    62. Watkins, L.R., et al., Norman Cousins Lecture. Glia as the "bad guys": implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun, 2007. 21(2): p. 131-46.
    63. Tsuda, M., et al., P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature, 2003. 424(6950): p. 778-83.
    64. Kast, B., The best supporting actors. Nature, 2001. 412(6848): p. 674-6.
    65. Ciccarelli, R., et al., Involvement of astrocytes in purine-mediated reparative processes in the brain. Int J Dev Neurosci, 2001. 19(4): p. 395-414.
    66.蔡文琴,刘.王.胡.杨.,星形胶质细胞.生理科学进展, 2004. 35(1): p. 86-91.
    67. Hundahl, C., et al., Does neuroglobin protect neurons from ischemic insult? A quantitative investigation of neuroglobin expression following transient MCAo in spontaneously hypertensive rats. Brain Res, 2006. 1085(1): p. 19-27.
    68. Mullen, R.J., C.R. Buck, and A.M. Smith, NeuN, a neuronal specific nuclear protein in vertebrates. Development, 1992. 116(1): p. 201-11.
    69. Vulchanova, L., et al., Immunohistochemical study of the P2X2 and P2X3 receptor subunits in rat and monkey sensory neurons and their central terminals. Neuropharmacology, 1997. 36(9): p. 1229-42.
    70. Nakatsuka, T., et al., Distinct roles of P2X receptors in modulating glutamate release at different primary sensory synapses in rat spinal cord. J Neurophysiol, 2003. 89(6): p. 3243-52.
    71. Paxinos , Watson, C., The Rat Brain in Stereotaxic Coordinates. Amsterdam: Academic Press, 2007.
    72. Day, M., et al., Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci, 2005. 25(38): p. 8776-87.
    73.赵延东,阮.,大鼠海马CA1区神经元P2X受体对ATP、suramin的反应.第三军医大学学报, 2005. 27(16): p. 1674-77.
    74. Bleehen, T. and C.A. Keele, Observations on the algogenic actions of adenosine compounds on the human blister base preparation. Pain, 1977. 3(4): p. 367-77.
    75. North, R.A., Molecular physiology of P2X receptors. Physiol Rev, 2002. 82(4): p. 1013-67.
    76. Parvizpur, A., A. Ahmadiani, and M. Kamalinejad, Probable role of spinal purinoceptors in the analgesic effect of Trigonella foenum (TFG) leaves extract. J Ethnopharmacol, 2006. 104(1-2): p. 108-12.
    77. Borsani, E., et al., PPADS, a purinergic antagonist reduces Fos expression at spinal cord level in a mouse model of mononeuropathy. Brain Res, 2008. 1199: p. 74-81.
    78. Migita, K., et al., Modulation of P2X receptors in dorsal root ganglion neurons of streptozotocin-induced diabetic neuropathy. Neurosci Lett, 2009. 452(2): p. 200-3.
    79. Distler, C., et al., Fast Ca2+-induced potentiation of heat-activated ionic currents requires cAMP/PKA signaling and functional AKAP anchoring. J Neurophysiol, 2003. 89(5): p. 2499-505.
    80. Lang, P.M., et al., Activation of adenosine and P2Y receptors by ATP in human peripheral nerve. Naunyn Schmiedebergs Arch Pharmacol, 2002. 366(5): p. 449-57.
    81. Bland-Ward, P.A. and P.P. Humphrey, Acute nociception mediated by hindpaw P2X receptor activation in the rat. Br J Pharmacol, 1997. 122(2): p. 365-71.
    82. Hamilton, S.G., S.B. McMahon, and G.R. Lewin, Selective activation of nociceptors by P2X receptor agonists in normal and inflamed rat skin. J Physiol, 2001. 534(Pt. 2): p. 437-45.
    83. Ruan, H.Z., E. Moules, and G. Burnstock, Changes in P2X3 purinoceptors in sensory ganglia of the mouse during embryonic and postnatal development. Histochem Cell Biol, 2004. 122(6): p. 539-51.
    84. Nakatsuka, T., et al., Depletion of substance P from rat primary sensory neurons by ATP, an implication of P2X receptor-mediated release of substance P. Neuroscience, 2001. 107(2): p. 293-300.
    85. Nakatsuka, T., et al., Activation of central terminal vanilloid receptor-1 receptors and alpha beta-methylene-ATP-sensitive P2X receptors reveals a converged synaptic activity onto the deep dorsal horn neurons of the spinal cord. J Neurosci, 2002. 22(4): p. 1228-37.
    86. Fukui, M., et al., Antinociceptive effects of intracerebroventricularly administered P2 purinoceptor agonists in the rat. Eur J Pharmacol, 2001. 419(1): p. 25-31.
    87. Jarvis, M.F., et al., A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc Natl Acad Sci U S A, 2002. 99(26): p. 17179-84.
    88. Wu, G., et al., A-317491, a selective P2X3/P2X2/3 receptor antagonist, reverses inflammatory mechanical hyperalgesia through action at peripheral receptors in rats. Eur J Pharmacol, 2004. 504(1-2): p. 45-53.
    89. McGaraughty, S., et al., Endogenous opioid mechanisms partially mediate P2X3/P2X2/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain. Br J Pharmacol, 2005. 146(2): p. 180-8.
    90. Gray, R. and D. Johnston, Rectification of single GABA-gated chloride channels in adult hippocampal neurons. J Neurophysiol, 1985. 54(1): p. 134-42.
    91. Inoue, K., et al., Extracellular adenosine 5'-triphosphate-evoked glutamate release in cultured hippocampal neurons. Neurosci Lett, 1992. 134(2): p. 215-8.
    92. Ueno, S., et al., ATP-gated current in dissociated rat nucleus solitarii neurons. J Neurophysiol, 1992. 68(3): p. 778-85.
    93. NIH Consensus Conference. Acupuncture. 1998. 280(17):: p. 1518-24.
    94. An, H.J., et al., Electroacupuncture protects against CCK-induced acute pancreatitis in rats. Neuroimmunomodulation, 2007. 14(2): p. 112-8.
    95. Han, J.S., Acupuncture and endorphins. Neurosci Lett, 2004. 361(1-3): p. 258-61.
    96. Zhao, F., L. Zhu, and Y. Li, [Therapeutic effects of electroacupuncture (EA) on acute experimental arthritis in rats]. Zhen Ci Yan Jiu, 1990. 15(3): p. 197-202.
    97. Zhao, Z.Q., Neural mechanism underlying acupuncture analgesia. Prog Neurobiol, 2008. 85(4): p. 355-75.
    98. Han, J.S., et al., Enkephalin and beta-endorphin as mediators of electro-acupuncture analgesia in rabbits: an antiserum microinjection study. Adv Biochem Psychopharmacol, 1982. 33: p. 369-77.
    99. Fang, J., [The influence of acupuncture at zusanli on cyclic nucleotide contents of plasma, different brain regions and spleen in rats]. Zhen Ci Yan Jiu, 1994. 19(1): p. 42-5.
    100. Lu, Z.S., et al., The relationship between cAMP and cGMP in regions of rat brain and acupuncture analgesia. J Tradit Chin Med, 1983. 3(1): p. 3-6.
    101.曲丽芳,环核苷酸在正常大鼠神阙、肾俞穴位组织内的分布及针刺后的变化.上海针灸杂志, 1999. 18(4): p. 36-37.
    102.贾君君,传统手针与电针对比研究现状.针灸临床杂志, 2007. 23(4): p. 62-63.
    103. Aloe, L. and L. Manni, Low-frequency electro-acupuncture reduces the nociceptive response and the pain mediator enhancement induced by nerve growth factor. Neurosci Lett, 2009. 449(3): p. 173-7.
    104. Lau, W.K., et al., Electroacupuncture inhibits cyclooxygenase-2 up-regulation in rat spinal cord after spinal nerve ligation. Neuroscience, 2008. 155(2): p. 463-8.
    105. Ko, J., et al., cDNA microarray analysis of the differential gene expression in the neuropathic pain and electroacupuncture treatment models. J Biochem Mol Biol, 2002. 35(4): p. 420-7.
    106.郭义,实验针灸学. 2008.中国中医药出版社.
    107. Liu, H.R., et al., Acupuncture at both ST25 and ST37 improves the pain threshold of chronic visceral hypersensitivity rats. Neurochem Res, 2009. 34(11): p. 1914-8.
    108. Sun, S., et al., Evidence for suppression of electroacupuncture on spinal glial activation and behavioral hypersensitivity in a rat model of monoarthritis. Brain Res Bull, 2008. 75(1): p. 83-93.
    109. Finnerup, N.B., et al., Algorithm for neuropathic pain treatment: an evidence based proposal. Pain, 2005. 118(3): p. 289-305.
    110. Attal, N., et al., EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol, 2006. 13(11): p. 1153-69.
    111. Oh, J.H., et al., Pain-relieving effects of acupuncture and electroacupuncture in an animal model of arthritic pain. Int J Neurosci, 2006. 116(10): p. 1139-56.
    112. Huang, C., et al., Ketamine potentiates the effect of electroacupuncture on mechanical allodynia in a rat model of neuropathic pain. Neuroscience Letters, 2004. 368(3): p. 327-331.
    113. Leem, J.W., E.S. Park, and K.S. Paik, Electrophysiological evidence for the antinociceptive effect of transcutaneous electrical stimulation on mechanically evoked responsiveness of dorsal horn neurons in neuropathic rats. Neurosci Lett, 1995. 192(3): p. 197-200.
    114. Kim, H.N., et al., Electroacupuncture potentiates the antiallodynic effect of intrathecal neostigmine in a rat model of neuropathic pain. J Physiol Sci, 2008. 58(5): p. 357-60.
    115. Han, J.-S., Terenius, L, Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci, 2003. 26: p. 17-22.
    116. Dong, Z.Q., et al., Effects of electroacupuncture on expression of somatostatin and preprosomatostatin mRNA in dorsal root ganglions and spinal dorsal horn in neuropathic pain rats. Neurosci Lett, 2005. 385(3): p. 189-94.
    117. Finnerup, N.B., S.H. Sindrup, and T.S. Jensen, Chronic neuropathic pain: mechanisms, drug targets and measurement. Fundam Clin Pharmacol, 2007. 21(2): p. 129-36.
    118. Jarvis, M.F. and J.M. Boyce-Rustay, Neuropathic pain: models and mechanisms. Curr Pharm Des, 2009. 15(15): p. 1711-6.
    119. Choi, B.T., J. Kang, and U.B. Jo, Effects of electroacupuncture with different frequencies on spinal ionotropic glutamate receptor expression in complete Freund's adjuvant-injected rat. Acta Histochem, 2005. 107(1): p. 67-76.
    120. Xing, G.G., et al., Long-term synaptic plasticity in the spinal dorsal horn and its modulation by electroacupuncture in rats with neuropathic pain. Exp Neurol, 2007. 208(2): p. 323-32.
    121. Ma, F., et al., Effects of electroacupuncture on orphanin FQ immunoreactivity and preproorphanin FQ mRNA in nucleus of raphe magnus in the neuropathic pain rats. Brain Res Bull, 2004. 63(6): p. 509-13.
    122. Sung, H.J., et al., Proteomic analysis of differential protein expression in neuropathic pain and electroacupuncture treatment models. Proteomics, 2004. 4(9): p. 2805-13.
    123. Fukui, M., et al., Inhibitory role of supraspinal P2X3/P2X2/3 subtypes on nociception in rats. Mol Pain, 2006. 2: p. 19.
    124. Burnstock, G., Acupuncture: a novel hypothesis for the involvement of purinergic signalling. Med Hypotheses, 2009. 73(4): p. 470-2.
    125. Burnstock, G., Cotransmission. Curr Opin Pharmacol, 2004. 4(1): p. 47-52.
    126. Salter, M.W. and J.L. Hicks, ATP-evoked increases in intracellular calcium in neurons and glia from the dorsal spinal cord. J Neurosci, 1994. 14(3 Pt 2): p. 1563-75.
    127. Sawynok, J., et al., ATP release from dorsal spinal cord synaptosomes: characterization and neuronal origin. Brain Res, 1993. 610(1): p. 32-8.
    128. Hamilton, N., et al., Axons and astrocytes release ATP and glutamate to evoke calcium signals in NG2-glia. Glia. 58(1): p. 66-79.
    129. Beitz, A.J., The organization of afferent projections to the midbrain periaqueductal gray of the rat. Neuroscience, 1982. 7(1): p. 133-59.
    130. Li, L., et al., The human brain response to acupuncture on same-meridian acupoints: evidence from an fMRI study. J Altern Complement Med, 2008. 14(6): p. 673-8.
    131.韩济生;,王.,不同穴位电针治疗大鼠慢性神经源性痛的疗效比较.针刺研究, 2002. 27(3): p. 180-185.
    132. Takeshige, C., et al., The acupuncture point and its connecting central pathway for producing acupuncture analgesia. Brain Res Bull, 1993. 30(1-2): p. 53-67.
    133. Liu, G.J. and S. Wang, [Effects of nucleus raphe magnus and locus coeruleus in descending modulation of the habenula on pain threshold and acupuncture analgesia]. Zhongguo Yao Li Xue Bao, 1988. 9(1): p. 18-22.
    134. Wu, C.-P., Chao, C-.C., Zhao, Z.-Q., Wei, J.-Y, Inhibitory effect produced by stimulation of afferent nerves on responses of cat dorsolateral fasciculus fibers to nocuous stimulus. Sci. Sin, 1974. XVII: p. 688-697.
    135.聂发华,电针治疗坐骨神经痛50例.新疆中医药, 1999. 17(2): p. 25-26.
    136.罗非,反复电针对慢性痛的累加治疗作用及其机制研究.生理科学进展, 1996. 7(3): p. 241-24.
    137. Yim, Y.K., et al., Electro-acupuncture at acupoint ST36 reduces inflammation andregulates immune activity in Collagen-Induced Arthritic Mice. Evid Based Complement Alternat Med, 2007. 4(1): p. 51-7.
    138. Takaoka, Y., et al., Electroacupuncture suppresses myostatin gene expression: cell proliferative reaction in mouse skeletal muscle. Physiol Genomics, 2007. 30(2): p. 102-10.
    139.韩济生,神经科学《第三版》.北京大学医学出版社, 2009.
    140. Wang, J.Y., et al., [Observation on the accumulative analgesic effect of electroacupuncture and the expression of protein kinase A in hypothalamus and hippocampus in chronic pain or/and ovariectomized rats]. Zhen Ci Yan Jiu, 2008. 33(2): p. 80-7.
    141. Ikeda, H., et al., Long-term potentiation of neuronal excitation by neuron-glia interactions in the rat spinal dorsal horn. Eur J Neurosci, 2007. 25(5): p. 1297-306.
    142. Butler, R.K. and D.P. Finn, Stress-induced analgesia. Prog Neurobiol, 2009. 88(3): p. 184-202.
    143. Shang, C., Prospective tests on biological models of acupuncture. Evid Based Complement Alternat Med, 2009. 6(1): p. 31-9.
    144. Shang, C., Electrophysiology of growth control and acupuncture. Life Sci, 2001. 68(12): p. 1333-42.
    145. Shang, C., Emerging paradigms in mind-body medicine. J Altern Complement Med, 2001. 7(1): p. 83-91.
    146. Wick, F., N. Wick, and M.C. Wick, Morphological analysis of human acupuncture points through immunohistochemistry. Am J Phys Med Rehabil, 2007. 86(1): p. 7-11.
    147. Kim, S.K., et al., A Parametric Study on the Immunomodulatory Effects of Electroacupuncture in DNP-KLH Immunized Mice. Evid Based Complement Alternat Med, 2009.
    148. Niu, W.X., et al., Effects and probable mechanisms of electroacupuncture at the Zusanli point on upper gastrointestinal motility in rabbits. J Gastroenterol Hepatol, 2007. 22(10): p. 1683-9.
    149. Farber, P.L., A. Tachibana, and H.M. Campiglia, Increased pain threshold following electroacupuncture: analgesia is induced mainly in meridian acupuncture points. Acupunct Electrother Res, 1997. 22(2): p. 109-17.
    150. Han, J.S., Zhou, Z., Xuan, Y., Acupuncture has an analgesic effect in rabbits. Pain, 1983. 15: p. 83-91.
    151.张俊海,穴位和非穴位电针镇痛的脑功能磁共振对照研究.中国医学计算机成像杂志, 2005. 11(1期): p. 10-13.
    152. Asghar, A.U., et al., Acupuncture needling sensation: the neural correlates of deqi using fMRI. Brain Res. 1315: p. 111-8.
    153. Dai, Y., et al., The effect of electroacupuncture on pain behaviors and noxious stimulus-evoked Fos expression in a rat model of neuropathic pain. J Pain, 2001. 2(3): p. 151-9.
    154. Hwang, B.G., et al., Effects of electroacupuncture on the mechanical allodynia in the rat model of neuropathic pain. Neurosci Lett, 2002. 320(1-2): p. 49-52.
    155. Kim, J.H., et al., Relieving effects of electroacupuncture on mechanical allodynia in neuropathic pain model of inferior caudal trunk injury in rat: mediation by spinal opioid receptors. Brain Res, 2004. 998(2): p. 230-6.
    156. Shimizu, I., et al., Enhanced thermal avoidance in mice lacking the ATP receptor P2X3. Pain, 2005. 116(1-2): p. 96-108.
    157. Sharp, C.J., et al., Investigation into the role of P2X(3)/P2X(2/3) receptors in neuropathic pain following chronic constriction injury in the rat: an electrophysiological study. Br J Pharmacol, 2006. 148(6): p. 845-52.
    158. Agrawal, S. and Q. Zhao, Antisense therapeutics. Curr Opin Chem Biol, 1998. 2(4): p. 519-28.
    159. Akhtar, S. and S. Agrawal, In vivo studies with antisense oligonucleotides. Trends Pharmacol Sci, 1997. 18(1): p. 12-8.
    160. Oka, T., et al., Effects of antisense oligodeoxynucleotides against opioid receptors on the receptor mRNA contents. Life Sci, 2001. 68(19-20): p. 2221-5.
    161. Maeda, T., et al., Morphine has an antinociceptive effect through activation of the okadaic-acid-sensitive Ser/Thr protein phosphatases PP 2 A and PP5 estimated by tail-pinch test in mice. Brain Res, 2005. 1056(2): p. 191-9.
    162. Oliveira, M.C., et al., Peripheral mechanisms underlying the essential role of P2X3,2/3 receptors in the development of inflammatory hyperalgesia. Pain, 2009. 141(1-2): p. 127-34.
    163. Zamecnik, P.C. and M.L. Stephenson, Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A, 1978. 75(1): p. 280-4.
    164. Sommer, W. and M. Heilig, [Antisense oligonucleotides are clinically tested. They inhibit the expression of disease-related genes]. Lakartidningen, 1999. 96(4): p. 348-54.
    165. Wahlestedt, C., et al., Antisense oligodeoxynucleotides to NMDA-R1 receptor channel protect cortical neurons from excitotoxicity and reduce focal ischaemic infarctions. Nature, 1993. 363(6426): p. 260-3.
    166. Ma, E., R. Morgan, and E.W. Godfrey, Agrin mRNA variants are differentially regulated in developing chick embryo spinal cord and sensory ganglia. J Neurobiol, 1995. 26(4): p. 585-97.
    167. Dina, O.A., et al., Mechanisms Mediating Vibration-induced Chronic Musculoskeletal Pain Analyzed in the Rat. J Pain, 2009.
    168. Zhang, L., et al., Activation of extracellular signal-regulated protein kinases 5 in the spinal cord contributes to the neuropathic pain behaviors induced by CCI in rats. Neurol Res, 2009. 31(10): p. 1037-43.
    169. Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain, 2002. 95(1-2): p. 143-52.
    170. Khasar, S.G., M.S. Gold, and J.D. Levine, A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat. Neurosci Lett, 1998. 256(1): p. 17-20.
    171. Song, M.J., Y.Q. Wang, and G.C. Wu, Additive anti-hyperalgesia of electroacupuncture and intrathecal antisense oligodeoxynucleotide to interleukin-1 receptor type I on carrageenan-induced inflammatory pain in rats. Brain Res Bull, 2009. 78(6): p. 335-41.
    172. Yang, J., et al., Transient receptor potential ankyrin-1 participates in visceral hyperalgesia following experimental colitis. Neurosci Lett, 2008. 440(3): p. 237-41.
    173. Shimoyama, N., et al., An antisense oligonucleotide to the N-methyl-D-aspartate (NMDA) subunit NMDAR1 attenuates NMDA-induced nociception, hyperalgesia, and morphine tolerance. J Pharmacol Exp Ther, 2005. 312(2): p. 834-40.
    174. Hemmings-Mieszczak, M., et al., Independent combinatorial effect of antisenseoligonucleotides and RNAi-mediated specific inhibition of the recombinant rat P2X3 receptor. Nucleic Acids Res, 2003. 31(8): p. 2117-26.
    175. Dorn, G., et al., Specific inhibition of the rat ligand-gated ion channel P2X3 function via methoxyethoxy-modified phosphorothioated antisense oligonucleotides. Antisense Nucleic Acid Drug Dev, 2001. 11(3): p. 165-74.
    176. Klein, G., et al., The contribution of MOR-1 exons 1-4 to morphine and heroin analgesia and dependence. Neurosci Lett, 2009. 457(3): p. 115-9.
    177. Mei, J. and G.W. Pasternak, Modulation of brainstem opiate analgesia in the rat by sigma 1 receptors: a microinjection study. J Pharmacol Exp Ther, 2007. 322(3): p. 1278-85.
    178. Blakley, G.G., L.A. Pohorecky, and D. Benjamin, Behavioral and endocrine changes following antisense oligonucleotide-induced reduction in the rat NOP receptor. Psychopharmacology (Berl), 2004. 171(4): p. 421-8.
    179. Bogen, O., et al., GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican. Eur J Neurosci, 2008. 28(1): p. 12-9.
    180. Malik-Hall, M., O.A. Dina, and J.D. Levine, Primary afferent nociceptor mechanisms mediating NGF-induced mechanical hyperalgesia. Eur J Neurosci, 2005. 21(12): p. 3387-94.
    181. Song, X.S., et al., Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats. Acta Pharmacol Sin, 2005. 26(7): p. 789-98.
    182. Shao, D., et al., A multi PDZ-domain protein Pdzd2 contributes to functional expression of sensory neuron-specific sodium channel Na(V)1.8. Mol Cell Neurosci, 2009. 42(3): p. 219-25.
    183. Lindia, J.A., et al., Relationship between sodium channel NaV1.3 expression and neuropathic pain behavior in rats. Pain, 2005. 117(1-2): p. 145-53.
    184. Wu, L.A., et al., Down-regulation of K+ -Cl- co-transporter 2 in mouse medullary dorsal horn contributes to the formalin-induced inflammatory orofacial pain. Neurosci Lett, 2009. 457(1): p. 36-40.
    185. Wang, W., et al., Crosstalk between spinal astrocytes and neurons in nerveinjury-induced neuropathic pain. PLoS One, 2009. 4(9): p. e6973.
    186. Lee, K.M., S.M. Jeon, and H.J. Cho, Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model. Eur J Pain, 2009. 13(8): p. 794-806.
    187. White, D.M., Neurotrophin-3 antisense oligonucleotide attenuates nerve injury-induced Abeta-fibre sprouting. Brain Res, 2000. 885(1): p. 79-86.
    188. Wang, T.T., et al., Effects of electro-acupuncture on the expression of c-jun and c-fos in spared dorsal root ganglion and associated spinal laminae following removal of adjacent dorsal root ganglia in cats. Neuroscience, 2006. 140(4): p. 1169-76.
    189. Jiang, K., et al., Electro-acupuncture preconditioning abrogates the elevation of c-Fos and c-Jun expression in neonatal hypoxic-ischemic rat brains induced by glibenclamide, an ATP-sensitive potassium channel blocker. Brain Res, 2004. 998(1): p. 13-9.
    190. Park, H.J., et al., Decrease of the electroacupuncture-induced analgesic effects in nuclear factor-kappa B1 knockout mice. Neurosci Lett, 2002. 319(3): p. 141-4.
    191. Jensen, T.S. and T.L. Yaksh, Spinal monoamine and opiate systems partly mediate the antinociceptive effects produced by glutamate at brainstem sites. Brain Res, 1984. 321(2): p. 287-97.
    192. Mason, P., Central mechanisms of pain modulation. Curr Opin Neurobiol, 1999. 9(4): p. 436-41.
    193. Okada, M., et al., Interaction between purinoceptor subtypes on hippocampal serotonergic transmission using in vivo microdialysis. Neuropharmacology, 1999. 38(5): p. 707-15.
    194. Fukui, M., et al., Involvement of locus coeruleus noradrenergic neurons in supraspinal antinociception by alpha,beta-methylene-ATP in rats. J Pharmacol Sci, 2004. 94(2): p. 153-60.
    195. Yao, S.T. and A.J. Lawrence, Purinergic modulation of cardiovascular function in the rat locus coeruleus. Br J Pharmacol, 2005. 145(3): p. 342-52.
    196. Fukui, M., et al., Involvement of beta2-adrenergic and mu-opioid receptors in antinociception produced by intracerebroventricular administration of alpha,beta-methylene-ATP. Jpn J Pharmacol, 2001. 86(4): p. 423-8.
    1. Cosens, D.J. and A. Manning, Abnormal electroretinogram from a Drosophila mutant. Nature, 1969. 224(5216): p. 285-7.
    2. Clapham, D.E., TRP channels as cellular sensors. Nature, 2003. 426(6966): p. 517-24.
    3. Montell, C., L. Birnbaumer, and V. Flockerzi, The TRP channels, a remarkably functional family. Cell, 2002. 108(5): p. 595-8.
    4. Oh, U., S.W. Hwang, and D. Kim, Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons. J Neurosci, 1996. 16(5): p. 1659-67.
    5. Guler, A.D., et al., Heat-evoked activation of the ion channel, TRPV4. J Neurosci, 2002. 22(15): p. 6408-14.
    6. Venkatachalam, K. and C. Montell, TRP channels. Annu Rev Biochem, 2007. 76: p. 387-417.
    7. Dhaka, A., V. Viswanath, and A. Patapoutian, Trp ion channels and temperature sensation. Annu Rev Neurosci, 2006. 29: p. 135-61.
    8. Caterina, M.J., et al., The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature, 1997. 389(6653): p. 816-24.
    9. Caterina, M.J., et al., A capsaicin-receptor homologue with a high threshold for noxious heat. Nature, 1999. 398(6726): p. 436-41.
    10. Xu, H., et al., TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature, 2002. 418(6894): p. 181-6.
    11. Smith, G.D., et al., TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature, 2002. 418(6894): p. 186-90.
    12. Peier, A.M., et al., A heat-sensitive TRP channel expressed in keratinocytes. Science, 2002. 296(5575): p. 2046-9.
    13. Story, G.M., et al., ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell, 2003. 112(6): p. 819-29.
    14. Peier, A.M., et al., A TRP channel that senses cold stimuli and menthol. Cell, 2002. 108(5): p. 705-15.
    15. McKemy, D.D., W.M. Neuhausser, and D. Julius, Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature, 2002. 416(6876): p. 52-8.
    16. Davis, K.D. and G.E. Pope, Noxious cold evokes multiple sensations with distinct time courses. Pain, 2002. 98(1-2): p. 179-85.
    17. Campbell, J.N. and R.H. LaMotte, Latency to detection of first pain. Brain Res, 1983.
    266(2): p. 203-8.
    18. Davis, J.B., et al., Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature, 2000. 405(6783): p. 183-7.
    19. Caterina, M.J., et al., Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 2000. 288(5464): p. 306-13.
    20. Kwan, K.Y., et al., TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron, 2006. 50(2): p. 277-89.
    21. Bautista, D.M., et al., TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell, 2006. 124(6): p. 1269-82.
    22. Moqrich, A., et al., Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science, 2005. 307(5714): p. 1468-72.
    23. Bautista, D.M., et al., The menthol receptor TRPM8 is the principal detector of environmental cold. Nature, 2007. 448(7150): p. 204-8.
    24. Colburn, R.W., et al., Attenuated cold sensitivity in TRPM8 null mice. Neuron, 2007. 54(3): p. 379-86.
    25. Dhaka, A., et al., TRPM8 is required for cold sensation in mice. Neuron, 2007. 54(3): p. 371-8.
    26. Holzer, P., Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev, 1991. 43(2): p. 143-201.
    27. Maione, S., et al., Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. J Pharmacol Exp Ther, 2006. 316(3): p. 969-82.
    28. Maione, S., et al., Functional interaction between TRPV1 and micro-opioid receptors in the descending antinociceptive pathway activates glutamate transmission and induces analgesia. J Neurophysiol, 2009. 101(5): p. 2411-22.
    29. Palazzo, E., F. Rossi, and S. Maione, Role of TRPV1 receptors in descending modulation of pain. Mol Cell Endocrinol, 2008. 286(1-2 Suppl 1): p. S79-83.
    30. McNamara, F.N., A. Randall, and M.J. Gunthorpe, Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1). Br J Pharmacol, 2005. 144(6): p. 781-90.
    31. Bautista, D.M., et al., Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci U S A, 2005. 102(34): p. 12248-52.
    32. Bandell, M., et al., Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron, 2004. 41(6): p. 849-57.
    33. Macpherson, L.J., et al., The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol, 2005. 15(10): p. 929-34.
    34. Jordt, S.E., et al., Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature, 2004. 427(6971): p. 260-5.
    35. Xu, H., N.T. Blair, and D.E. Clapham, Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism. J Neurosci, 2005. 25(39): p. 8924-37.
    36. Alessandri-Haber, N., et al., Hypotonicity induces TRPV4-mediated nociception in rat. Neuron, 2003. 39(3): p. 497-511.
    37. Alessandri-Haber, N., et al., Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci, 2004. 24(18): p. 4444-52.
    38. Welch, J.M., S.A. Simon, and P.H. Reinhart, The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat. Proc Natl Acad Sci U S A, 2000. 97(25): p. 13889-94.
    39. Tominaga, M., et al., The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron, 1998. 21(3): p. 531-43.
    40. Aloe, L. and L. Manni, Low-frequency electro-acupuncture reduces the nociceptive response and the pain mediator enhancement induced by nerve growth factor. Neurosci Lett, 2009. 449(3): p. 173-7.
    41. Ferreira, J., G.L. da Silva, and J.B. Calixto, Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice. Br J Pharmacol, 2004. 141(5): p. 787-94.
    42. Hwang, S.W., et al., Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci U S A, 2000. 97(11): p. 6155-60.
    43. Chuang, H.H., et al., Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature, 2001. 411(6840): p. 957-62.
    44. Prescott, E.D. and D. Julius, A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science, 2003. 300(5623): p. 1284-8.
    45. Premkumar, L.S. and G.P. Ahern, Induction of vanilloid receptor channel activity by protein kinase C. Nature, 2000. 408(6815): p. 985-90.
    46. Sugiura, T., et al., Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. J Neurophysiol, 2002. 88(1): p. 544-8.
    47. Reeh, P.W. and M. Kress, Molecular physiology of proton transduction in nociceptors. Curr Opin Pharmacol, 2001. 1(1): p. 45-51.
    48. Reeh, P.W. and K.H. Steen, Tissue acidosis in nociception and pain. Prog Brain Res, 1996. 113: p. 143-51.
    49. Kellenberger, S. and L. Schild, Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol Rev, 2002. 82(3): p. 735-67.
    50. Bassler, E.L., et al., Molecular and functional characterization of acid-sensing ion channel (ASIC) 1b. J Biol Chem, 2001. 276(36): p. 33782-7.
    51. Baron, A., et al., Zn2+ and H+ are coactivators of acid-sensing ion channels. J Biol Chem, 2001. 276(38): p. 35361-7.
    52. Chen, C.C., et al., A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci U S A, 1998. 95(17): p. 10240-5.
    53. Lingueglia, E., et al., A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J Biol Chem, 1997. 272(47): p. 29778-83.
    54. Ugawa, S., et al., Cloning and functional expression of ASIC-beta2, a splice variant of ASIC-beta. Neuroreport, 2001. 12(13): p. 2865-9.
    55. Waldmann, R., et al., Molecular cloning of a non-inactivating proton-gated Na+ channel specific for sensory neurons. J Biol Chem, 1997. 272(34): p. 20975-8.
    56. Mamet, J., M. Lazdunski, and N. Voilley, How nerve growth factor drives physiological and inflammatory expressions of acid-sensing ion channel 3 in sensory neurons. J Biol Chem, 2003. 278(49): p. 48907-13.
    57. Steen, K.H., A.E. Steen, and P.W. Reeh, A dominant role of acid pH in inflammatory excitation and sensitization of nociceptors in rat skin, in vitro. J Neurosci, 1995. 15(5 Pt 2): p. 3982-9.
    58. Mamet, J., et al., Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci, 2002. 22(24): p. 10662-70.
    59. Mazzuca, M., et al., A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nat Neurosci, 2007. 10(8): p. 943-5.
    60. Benveniste, M. and R. Dingledine, Limiting stroke-induced damage by targeting an acid channel. N Engl J Med, 2005. 352(1): p. 85-6.
    61. Sluka, K.A., et al., Chronic hyperalgesia induced by repeated acid injections in muscleis abolished by the loss of ASIC3, but not ASIC1. Pain, 2003. 106(3): p. 229-39.
    62. Sutherland, S.P., et al., Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc Natl Acad Sci U S A, 2001. 98(2): p. 711-6.
    63. Immke, D.C. and E.W. McCleskey, Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat Neurosci, 2001. 4(9): p. 869-70.
    64. Benson, C.J., S.P. Eckert, and E.W. McCleskey, Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic sensation. Circ Res, 1999. 84(8): p. 921-8.
    65. Drury, A.N. and A. Szent-Gyorgyi, The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol, 1929. 68(3): p. 213-37.
    66. Holton, P., The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol, 1959. 145(3): p. 494-504.
    67. Burnstock, G., et al., Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut. Br J Pharmacol, 1970. 40(4): p. 668-88.
    68. Burnstock, G., et al., Direct evidence for ATP release from non-adrenergic, non-cholinergic ("purinergic") nerves in the guinea-pig taenia coli and bladder. Eur J Pharmacol, 1978. 49(2): p. 145-9.
    69. Burnstock, G., A basis for distinguishing two types of purinergic receptor. In Cell Membrane Receptors for Drugs and Hormones: A Multidisciplinary Approach Straub, R.W. and Bolis, L.,eds, 1978: p. 107–118.
    70. Burnstock, G., Historical review: ATP as a neurotransmitter. Trends Pharmacol Sci, 2006. 27(3): p. 166-76.
    71. Chen, C.C., et al., A P2X purinoceptor expressed by a subset of sensory neurons. Nature, 1995. 377(6548): p. 428-31.
    72. Ruan, H.Z., et al., Localization of P2X and P2Y receptors in dorsal root ganglia of the cat. J Histochem Cytochem, 2005. 53(10): p. 1273-82.
    73. Collo, G., et al., Cloning OF P2X5 and P2X6 receptors and the distribution andproperties of an extended family of ATP-gated ion channels. J Neurosci, 1996. 16(8): p. 2495-507.
    74. Worthington, R.A., et al., Identification and localisation of ATP P2X receptors in rat midbrain. Electrophoresis, 1999. 20(10): p. 2077-80.
    75. Close, L.N., et al., Purinergic receptor immunoreactivity in the rostral ventromedial medulla. Neuroscience, 2009. 158(2): p. 915-21.
    76. Tsuzuki, K., et al., TNP-ATP-resistant P2X ionic current on the central terminals and somata of rat primary sensory neurons. J Neurophysiol, 2003. 89(6): p. 3235-42.
    77. Cockayne, D.A., et al., Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature, 2000. 407(6807): p. 1011-5.
    78. Souslova, V., et al., Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature, 2000. 407(6807): p. 1015-7.
    79. Liu, P.S. and Y.Y. Chen, Butyl benzyl phthalate blocks Ca2+ signaling coupled with purinoceptor in rat PC12 cells. Toxicol Appl Pharmacol, 2006. 210(1-2): p. 136-41.
    80. Burnstock, G., The past, present and future of purine nucleotides as signalling molecules. Neuropharmacology, 1997. 36(9): p. 1127-39.
    81. Kennedy, C. and P. Leff, Painful connection for ATP. Nature, 1995. 377(6548): p. 385-6.
    82. Bleehen, T. and C.A. Keele, Observations on the algogenic actions of adenosine compounds on the human blister base preparation. Pain, 1977. 3(4): p. 367-77.
    83. Bland-Ward, P.A. and P.P. Humphrey, Acute nociception mediated by hindpaw P2X receptor activation in the rat. Br J Pharmacol, 1997. 122(2): p. 365-71.
    84. Hamilton, S.G. and S.B. McMahon, ATP as a peripheral mediator of pain. J Auton Nerv Syst, 2000. 81(1-3): p. 187-94.
    85. Krishtal, O.A., S.M. Marchenko, and V.I. Pidoplichko, Receptor for ATP in the membrane of mammalian sensory neurones. Neurosci Lett, 1983. 35(1): p. 41-5.
    86. Bean, B.P., ATP-activated channels in rat and bullfrog sensory neurons: concentration dependence and kinetics. J Neurosci, 1990. 10(1): p. 1-10.
    87. Hamilton, S.G., et al., ATP in human skin elicits a dose-related pain response which ispotentiated under conditions of hyperalgesia. Brain, 2000. 123 ( Pt 6): p. 1238-46.
    88. Hamilton, S.G., ATP and pain. Pain Pract, 2002. 2(4): p. 289-94.
    89. Khakh, B.S. and R.A. North, P2X receptors as cell-surface ATP sensors in health and disease. Nature, 2006. 442(7102): p. 527-32.
    90. Cook, S.P. and E.W. McCleskey, Cell damage excites nociceptors through release of cytosolic ATP. Pain, 2002. 95(1-2): p. 41-7.
    91. Hoyle, C.H., Non-adrenergic, non-cholinergic control of the urinary bladder. World J Urol, 1994. 12(5): p. 233-44.
    92. Jo, Y.H. and R. Schlichter, Synaptic corelease of ATP and GABA in cultured spinal neurons. Nat Neurosci, 1999. 2(3): p. 241-5.
    93. Xu, G.Y. and L.Y. Huang, Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci, 2002. 22(1): p. 93-102.
    94. Ramer, M.S., E.J. Bradbury, and S.B. McMahon, Nerve growth factor induces P2X(3) expression in sensory neurons. J Neurochem, 2001. 77(3): p. 864-75.
    95. Paukert, M., et al., Inflammatory mediators potentiate ATP-gated channels through the P2X(3) subunit. J Biol Chem, 2001. 276(24): p. 21077-82.
    96. Dorn, G., et al., siRNA relieves chronic neuropathic pain. Nucleic Acids Res, 2004. 32(5): p. e49.
    97. Honore, P., et al., Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain, 2002. 99(1-2): p. 11-9.
    98. Barclay, J., et al., Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain. J Neurosci, 2002. 22(18): p. 8139-47.
    99. Jarvis, M.F., et al., A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc Natl Acad Sci U S A, 2002. 99(26): p. 17179-84.
    100. Chen, Y., et al., Mechanisms underlying enhanced P2X receptor-mediated responses in the neuropathic pain state. Pain, 2005. 119(1-3): p. 38-48.
    101. Fukui, M., et al., Inhibitory role of supraspinal P2X3/P2X2/3 subtypes on nociception in rats. Mol Pain, 2006. 2: p. 19.
    102. Cockayne, D.A., et al., P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J Physiol, 2005. 567(Pt 2): p. 621-39.
    103. Tsuda, M., et al., P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature, 2003. 424(6950): p. 778-83.
    104. Guo, L.H., K. Trautmann, and H.J. Schluesener, Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain. J Neuroimmunol, 2005. 163(1-2): p. 120-7.
    105. Honore,P., et al.,A-740003[N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino} -2,2- dimethylpropyl) -2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. J Pharmacol Exp Ther, 2006. 319(3): p. 1376-85.
    106. Chessell, I.P., et al., Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain, 2005. 114(3): p. 386-96.
    107. Abbracchio, M.P., et al., Characterization of the UDP-glucose receptor (re-named here the P2Y14 receptor) adds diversity to the P2Y receptor family. Trends Pharmacol Sci, 2003. 24(2): p. 52-5.
    108. Usachev, Y.M., et al., Bradykinin and ATP accelerate Ca(2+) efflux from rat sensory neurons via protein kinase C and the plasma membrane Ca(2+) pump isoform 4. Neuron, 2002. 33(1): p. 113-22.
    109. Florenzano, F., et al., The role of ionotropic purinergic receptors (P2X) in mediating plasticity responses in the central nervous system. Adv Exp Med Biol, 2006. 557: p. 77-100.
    110. Moriyama, T., et al., Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity. J Neurosci, 2003. 23(14): p. 6058-62.
    111. Okada, M., et al., Analgesic effects of intrathecal administration of P2Y nucleotidereceptor agonists UTP and UDP in normal and neuropathic pain model rats. J Pharmacol Exp Ther, 2002. 303(1): p. 66-73.
    112. Molliver, D.C., et al., ATP and UTP excite sensory neurons and induce CREB phosphorylation through the metabotropic receptor, P2Y2. Eur J Neurosci, 2002. 16(10): p. 1850-60.
    113. Gu, J.G. and A.B. MacDermott, Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature, 1997. 389(6652): p. 749-53.
    114. Li, P., A.A. Calejesan, and M. Zhuo, ATP P2x receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats. J Neurophysiol, 1998. 80(6): p. 3356-60.
    115. Khakh, B.S. and G. Henderson, ATP receptor-mediated enhancement of fast excitatory neurotransmitter release in the brain. Mol Pharmacol, 1998. 54(2): p. 372-8.
    116. Fellin, T., T. Pozzan, and G. Carmignoto, Purinergic receptors mediate two distinct glutamate release pathways in hippocampal astrocytes. J Biol Chem, 2006. 281(7): p. 4274-84.
    117. Xing, J., J. Lu, and J. Li, Purinergic P2X receptors presynaptically increase glutamatergic synaptic transmission in dorsolateral periaqueductal gray. Brain Res, 2008. 1208: p. 46-55.
    118. Jo, Y.H. and L.W. Role, Coordinate release of ATP and GABA at in vitro synapses of lateral hypothalamic neurons. J Neurosci, 2002. 22(12): p. 4794-804.
    119. Kang, T.C., et al., P2X2 and P2X4 receptor expression is regulated by a GABA(A) receptor-mediated mechanism in the gerbil hippocampus. Brain Res Mol Brain Res, 2003. 116(1-2): p. 168-75.
    120. Waldron, J.B. and J. Sawynok, Peripheral P2X receptors and nociception: interactions with biogenic amine systems. Pain, 2004. 110(1-2): p. 79-89.
    121. Nakatsuka, T., et al., Depletion of substance P from rat primary sensory neurons by ATP, an implication of P2X receptor-mediated release of substance P. Neuroscience, 2001. 107(2): p. 293-300.
    122. Lesage, F., et al., TWIK-1, a ubiquitous human weakly inward rectifying K+ channelwith a novel structure. EMBO J, 1996. 15(5): p. 1004-11.
    123. Kang, D., C. Choe, and D. Kim, Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. J Physiol, 2005. 564(Pt 1): p. 103-16.
    124. Maingret, F., et al., TREK-1 is a heat-activated background K(+) channel. EMBO J, 2000. 19(11): p. 2483-91.
    125. Alloui, A., et al., TREK-1, a K+ channel involved in polymodal pain perception. EMBO J, 2006. 25(11): p. 2368-76.
    126. Honore, E., The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci, 2007. 8(4): p. 251-61.
    127. Lesage, F., F. Maingret, and M. Lazdunski, Cloning and expression of human TRAAK, a polyunsaturated fatty acids-activated and mechano-sensitive K(+) channel. FEBS Lett, 2000. 471(2-3): p. 137-40.
    128. Honore, E., et al., Desensitization of mechano-gated K2P channels. Proc Natl Acad Sci U S A, 2006. 103(18): p. 6859-64.
    129. Honore, E., et al., An intracellular proton sensor commands lipid- and mechano-gating of the K(+) channel TREK-1. EMBO J, 2002. 21(12): p. 2968-76.
    130. Lesage, F., et al., Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. J Biol Chem, 2000. 275(37): p. 28398-405.
    131. Maingret, F., et al., Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. J Biol Chem, 1999. 274(38): p. 26691-6.
    132. Patel, A.J., et al., Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci, 1999. 2(5): p. 422-6.
    133. Goldin, A.L., et al., Nomenclature of voltage-gated sodium channels. Neuron, 2000. 28(2): p. 365-8.
    134. Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62.
    135. Dib-Hajj, S.D., et al., NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. ProcNatl Acad Sci U S A, 1998. 95(15): p. 8963-8.
    136. Chung K, C.J., Voltage-gated sodium channels and neuropathic pain. The nociceptive membrane. Amsterdam: Academic Press;, 2006: p. 312–321.
    137. Waxman, S.G., J.D. Kocsis, and J.A. Black, Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy. J Neurophysiol, 1994. 72(1): p. 466-70.
    138. Boucher, T.J., et al., Potent analgesic effects of GDNF in neuropathic pain states. Science, 2000. 290(5489): p. 124-7.
    139. Kim, C.H., et al., The changes in expression of three subtypes of TTX sensitive sodium channels in sensory neurons after spinal nerve ligation. Brain Res Mol Brain Res, 2001. 95(1-2): p. 153-61.
    140. Kim, C.H., et al., Changes in three subtypes of tetrodotoxin sensitive sodium channel expression in the axotomized dorsal root ganglion in the rat. Neurosci Lett, 2002. 323(2): p. 125-8.
    141. Akopian, A.N., et al., The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci, 1999. 2(6): p. 541-8.
    142. Porreca, F., et al., A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc Natl Acad Sci U S A, 1999. 96(14): p. 7640-4.
    143. Gold, M.S., et al., Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. J Neurosci, 2003. 23(1): p. 158-66.
    144. Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain, 2002. 95(1-2): p. 143-52.
    145. Kretschmer, T., et al., Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry. Acta Neurochir (Wien), 2002. 144(8): p. 803-10; discussion 810.
    146. Ji, H.L. and T.Y. Wang, Puerarin inhibits tetrodotoxin-resistant sodium current in rat dorsal root ganglion neurons. Zhongguo Yao Li Xue Bao, 1996. 17(2): p. 115-8.
    147. Kohane, D.S., et al., Vanilloid receptor agonists potentiate the in vivo local anestheticactivity of percutaneously injected site 1 sodium channel blockers. Anesthesiology, 1999. 90(2): p. 524-34.
    148. Lai, J., et al., Voltage-gated sodium channels and hyperalgesia. Annu Rev Pharmacol Toxicol, 2004. 44: p. 371-97.
    149. Mao, J. and L.L. Chen, Systemic lidocaine for neuropathic pain relief. Pain, 2000. 87(1): p. 7-17.
    150. Chaplan, S.R., J.W. Pogrel, and T.L. Yaksh, Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. J Pharmacol Exp Ther, 1994. 269(3): p. 1117-23.
    151. Hatakeyama, S., et al., Differential nociceptive responses in mice lacking the alpha(1B) subunit of N-type Ca(2+) channels. Neuroreport, 2001. 12(11): p. 2423-7.
    152. Kim, C., et al., Altered nociceptive response in mice deficient in the alpha(1B) subunit of the voltage-dependent calcium channel. Mol Cell Neurosci, 2001. 18(2): p. 235-45.
    153. Saegusa, H., et al., Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2+ channel. EMBO J, 2001. 20(10): p. 2349-56.
    154. Sah, P. and E.S. Faber, Channels underlying neuronal calcium-activated potassium currents. Prog Neurobiol, 2002. 66(5): p. 345-53.
    155. Bowersox, S.S., et al., Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain. J Pharmacol Exp Ther, 1996. 279(3): p. 1243-9.
    156. Sluka, K.A., Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation. J Pharmacol Exp Ther, 1998. 287(1): p. 232-7.
    157. Brose, W.G., et al., Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain. Clin J Pain, 1997. 13(3): p. 256-9.
    158. Neugebauer, V., et al., Effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint. J Neurophysiol, 1996. 76(6): p. 3740-9.
    159. Scott, D.A., C.E. Wright, and J.A. Angus, Actions of intrathecal omega-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. Eur J Pharmacol, 2002. 451(3): p. 279-86.
    160. Snutch, T.P., Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx, 2005. 2(4): p. 662-70.
    161. Winquist, R.J., J.Q. Pan, and V.K. Gribkoff, Use-dependent blockade of Cav2.2 voltage-gated calcium channels for neuropathic pain. Biochem Pharmacol, 2005. 70(4): p. 489-99.
    162. Gee, N.S., et al., The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem, 1996. 271(10): p. 5768-76.
    163. Wang, M., et al., Structural requirement of the calcium-channel subunit alpha2delta for gabapentin binding. Biochem J, 1999. 342 ( Pt 2): p. 313-20.
    164. Richter, R.W., et al., Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain, 2005. 6(4): p. 253-60.
    165. van Seventer, R., et al., Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial. Curr Med Res Opin, 2006. 22(2): p. 375-84.
    166. Siddall, P.J., et al., Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology, 2006. 67(10): p. 1792-800.
    1. Liu, X.A., et al., [Role of afferent C fibers in electroacupuncture of "zusanli" point in activating nucleus raphe magnus]. Sheng Li Xue Bao, 1990. 42(6): p. 523-33.
    2. Liu, X., B. Zhu, and S.X. Zhang, Relationship between electroacupuncture analgesia and descending pain inhibitory mechanism of nucleus raphe magnus. Pain, 1986. 24(3): p. 383-96.
    3. Zhu, L., et al., The effect of neonatal capsaicin on acupuncture analgesia--to evaluate the role of C fibers in acupuncture analgesia. Zhen Ci Yan Jiu, 1990. 15(4): p. 285-91.
    4.徐嵘,关新民,王才源,辣椒素处理坐骨神经对大鼠痛阈和电针镇痛效应的影响.针刺研究, 1993. 18(4): p. 280-284.
    5.张晏平,张志坚,梁勋厂,硬脊膜外注射辣椒素对大鼠痛阈及电针镇痛效应的影响.针刺研究, 1990. 15(2): p. 130-135.
    6.包虹,周正锋,于英心, C纤维不是电针镇痛的主要传入纤维,而是弥漫性伤害性抑制控制的主要纤维.针刺研究, 1991. 16(2): p. 120-124.
    7.陆卓珊,曹蔚鸿,董晓彤,辣椒素敏感神经元针刺镇痛效应的关系.针刺研究, 1990. 15(3): p. 213-216.
    8. Chung, J.M., et al., Prolonged inhibition of primate spinothalamic tract cells by peripheral nerve stimulation. Pain, 1984. 19(3): p. 259-75.
    9. Kawakita, K. and M. Funakoshi, Suppression of the jaw-opening reflex by conditioning a-delta fiber stimulation and electroacupuncture in the rat. Exp Neurol, 1982. 78(2): p. 461-5.
    10. Leung, A., et al., The effect of Ting point (tendinomuscular meridians)electroacupuncture on thermal pain: a model for studying the neuronal mechanism of acupuncture analgesia. J Altern Complement Med, 2005. 11(4): p. 653-61.
    11. Toda, K., Afferent nerve characteristics during acupuncture stimulation. Int. Congress Ser, 2002. 1238: p. 49-61.
    12. Jarvis, M.F. and J.M. Boyce-Rustay, Neuropathic pain: models and mechanisms. Curr Pharm Des, 2009. 15(15): p. 1711-6.
    13. Finnerup, N.B., S.H. Sindrup, and T.S. Jensen, Chronic neuropathic pain: mechanisms, drug targets and measurement. Fundam Clin Pharmacol, 2007. 21(2): p. 129-36.
    14. Wu, C.-P., Chao, C-.C., Zhao, Z.-Q., Wei, J.-Y, Inhibitory effect produced by stimulation of afferent nerves on responses of cat dorsolateral fasciculus fibers to nocuous stimulus. Sci. Sin, 1974. XVII: p. 688-697.
    15.阮怀珍,李.,蔡文琴., 5-羟色胺和生长抑素对P物质及慢痛引起的脊髓背角神经元电活动的影响.针刺研究, 1996. 21(3): p. 27-31.
    16.边景檀,脊髓中P物质与电针镇痛的研究.生理科学进展1995. 26(4): p. 325-328.
    17.魏锋,脊髓背角痛觉传递和调制的一些化学解剖学观察.生理科学进展, 1996. 27(4): p. 327-330.
    18.田学锋,阿片肽及有关因素在脊髓损伤中的作用.生理科学进展, 1992. 23(3): p.
    214-218.
    19.张香桐,针刺镇痛过程中丘脑的整合作用.中国科学, 1993(1): p. 28.
    20.韩济生,针刺镇痛及其有关的神经通路和神经介质.生理科学进展1984. 15(4): p.
    294.
    21.赵邦云,中脑导水管周围灰质和海马在ACTH镇痛中的相互关系.神经科学, 1996. 3(1): p. 28.
    22. Liu, X., [The modulation of cerebral cortex and subcortical nuclei on NRM and their role in acupuncture analgesia]. Zhen Ci Yan Jiu, 1996. 21(1): p. 4-11.
    23.邹捷,中缝大核神经元与伤害性运动反射的关系.针刺研究, 1990. 15(3): p. 159.
    24.韩济生,强啡肽在大鼠脊髓内的强烈镇痛作用.中国科学医辑, 1983. 11: p. 1014.
    25.于龙川,家兔下丘脑弓状核参与伏核到中脑导水管周围灰质的下行镇痛通路.生理学报, 1988 40(2): p. 123.
    26.刘乡,大脑皮层和皮层下核团对中缝大核的调控及其在针刺镇痛中的作用.针刺研究, 1996. 21(1): p. 40.
    27.董艺娜,中枢去甲肾上腺素和强啡肽A(17)在痛觉调制中的相互作用.中国疼痛医学杂志1997. 3(1): p. 38.
    28. Mason, P., Central mechanisms of pain modulation. Curr Opin Neurobiol, 1999. 9(4): p. 436-41.
    29.田震东,蓝斑在刺激视上核镇痛中的作用.生理学报, 1995. 47(4): p. 320.
    30. Wang, S., et al., [Effects of exciting the habenula by L-glutamic acid on the pain threshold and acupuncture analgesia]. Zhongguo Yao Li Xue Bao, 1987. 8(3): p. 200-3.
    31. Liu, G.J. and S. Wang, [Effects of nucleus raphe magnus and locus coeruleus in descending modulation of the habenula on pain threshold and acupuncture analgesia]. Zhongguo Yao Li Xue Bao, 1988. 9(1): p. 18-22.
    32.韩济生,内源性镇痛系统.生理科学进展, 1981. 12(2): p. 104.
    33.马素平,中脑边缘镇痛调制中的作用.生理科学进展, 1991. 22(3): p. 249.
    34. Zangen, A., R. Nakash, and G. Yadid, Serotonin-mediated increases in the extracellular levels of beta-endorphin in the arcuate nucleus and nucleus accumbens: a microdialysis study. J Neurochem, 1999. 73(6): p. 2569-74.
    35. Xuan, Y.T., et al., Studies on the mesolimbic loop of antinociception--II. A serotonin-enkephalin interaction in the nucleus accumbens. Neuroscience, 1986. 19(2): p. 403-9.
    36.陈向阳,中缝核参与下丘脑弓状核对丘脑束旁核痛单位放电的抑制.生理学报, 1987. 39(1): p. 46.
    37.马青年,中脑边缘镇痛的神经化学和形态研究.生理科学进展, 1991. 22(3): p. 248.
    38. Pert, C.B., M.J. Kuhar, and S.H. Snyder, Opiate receptor: autoradiographic localization in rat brain. Proc Natl Acad Sci U S A, 1976. 73(10): p. 3729-33.
    39. Dong, W.-Q., He, L.-F., Wang, M.-Z., Li, K.-Y., Huang, X.-F., Effects of iontophoretic etrophine and electroacupuncture on evoked neuronal response in anterior nuclei of rabbits’thalamus. Chin. J. Physiol. Sci 1987. 3: p. 244-250.
    40.张俊海,穴位和非穴位电针镇痛的脑功能磁共振对照研究.中国医学计算机成像杂志, 2005. 11(1期): p. 10-13.
    41. Wu, M.T., Hsieh, J.C., Xiong, J., Yang, C.F., Pan, H.B., Chen, Y.C., Tsai, G., Rosen, B.R.,Kwong, K.K., Central nervous pathway for acupuncture stimulation: localization of processing with functional MR imaging of the brain—preliminary experience. Radiology 1999. 212: p. 133-141.
    42.朱崇斌,孤啡肽拮抗针刺镇痛及阿片镇痛.针刺研究, 1997. 22(1,2): p. 36.
    43.林郁,大脑皮层参与疼痛的调节.生理科学进展, 1985. 16(1): p. 13.
    44. Stein, C., M. Schafer, and H. Machelska, Attacking pain at its source: new perspectives on opioids. Nat Med, 2003. 9(8): p. 1003-8.
    45. Sekido, R., K. Ishimaru, and M. Sakita, Differences of electroacupuncture-induced analgesic effect in normal and inflammatory conditions in rats. Am J Chin Med, 2003. 31(6): p. 955-65.
    46. Zhang, G.G., et al., Involvement of peripheral opioid mechanisms in electroacupuncture analgesia. Explore (NY), 2005. 1(5): p. 365-71.
    47.何莲芳,高.,福尔马林致痛提高大鼠中枢μ阿片受体密度及电针刺的加强作用.生理学报, 1996. 48(2): p. 125-131.
    48. Romita, V.V., A. Suk, and J.L. Henry, Parametric studies on electroacupuncture-like stimulation in a rat model: effects of intensity, frequency, and duration of stimulation on evoked antinociception. Brain Res Bull, 1997. 42(4): p. 289-96.
    49. Romita, V.V. and J.L. Henry, Spinal mu-, delta- and kappa-opioid receptors mediate intense stimulation-elicited inhibition of a nociceptive reflex in the rat. Eur J Pharmacol, 1998. 357(2-3): p. 127-38.
    50. Han, J.-S., Terenius, L, Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci, 2003. 26: p. 17-22.
    51. Han, J.S., et al., Effect of low- and high-frequency TENS on Met-enkephalin-Arg-Phe and dynorphin A immunoreactivity in human lumbar CSF. Pain, 1991. 47(3): p. 295-8.
    52.黄显奋,阿.,育亨宾鞘内注射对电针镇痛及脑内β一内啡肽释放的抑制.针刺研究, 1996. 21(1): p. 52-55.
    53.徐嵘,关.,王才源,电针及辣椒素处理对脊髓后角ACHE活性和[3H]一QNB结合位点的影响.针刺研究, 1996. 21(2): p. 47-51.
    54.关新民,针刺痛时脊髓后和脊神经节内Ach代谢的变化.针刺研究, 1990. 15(1): p. 18-23.
    55.关新民,王.,余福,中枢乙酰胆碱与针刺镇痛关系的研究.针刺研究, 1991. 16(2): p. 129-137.
    56.沈上,边景檀,电针引起脊髓P物质释放的频率依赖性.生理学报1996. 48(1): p. 89-93.
    57.边景檀,脊髓中P物质参与电针镇痛的研究.生理科学进展, 1995. 26(4): p. 325-328.
    58.黎春元,朱.李.,针刺的突触前去极化效应与γ一氨基丁酸,内阿片肽,P物质的关系.针刺研究, 1993. 18(2): p. 178-182.
    59. Millan, M.J., Descending control of pain. Prog Neurobiol, 2002. 66(6): p. 355-474.
    60. Liu, F.Y., Xing, G.G., Qu, X.X., Xu, I.S., Han, J.S., Wan, Y., Roles of 5-hydro-xytryptamine (5-HT) receptor subtypes in the inhibitory effects of 5-HT on C-fiber responses of spinal wide dynamic range neurons in rats. J. Pharmacol. Exp.Ther, 2007. 321: p. 1046-1053.
    61. Zhu, C.B., Xu, S.F., Wu, G.C., Cao, X.D., Research on combination of acupuncture with drugs. World J. Acupunct. Moxib, 1997. 7(54-59).
    62. Zhu, C.-B., Li, X.-Y., Zhu, Y.-H., Wu, G.-C., Xu, S.-F, Alteration of monoamine contents in microdialysate following droperidol enhanced electroacupuncture. Acta Physiol. Sin, 1997. 49: p. 382-388.
    63. Han, J.-S., Terenius, L, Neurochemical basis of acupuncture analgesia. Ann.Rev. Pharmacol. Toxicol, 1982. 22: p. 193-220.
    64. Li, X.Y., et al., Expressions of preproenkephalin mRNA during electroacupuncture analgesia enhanced by fenfluramine. Zhongguo Yao Li Xue Bao, 1995. 16(5): p. 431-4.
    65.王力萍,李肇春,关新民,大鼠C纤维在电针镇痛中与脊髓内5一羟色胺的关系.针刺研究, 1995. 20(3): p. 13-17.
    66. Li, A.-H., Hwang, H.M., Tan, P.P., Wu, T., Wang, H.L, Neurotensin excites periaqueductal gray neurons projecting to the rostral ventromedial medulla. Neurophysiol, 2001. 85: p. 1479-1488.
    67. Tershner, S.A., Helmstetter, F.J, Antinociception produced by mu opioid receptor activation in the amygdala is partly dependent on activation of mu opioid and neurotensin receptors in the ventral periaqueductal gray. Brain Res, 2000. 865: p. 17-26.
    68.刘文彦,白.,王宏,大鼠脊髓蛛网膜下腔注射神经降压素对针刺镇痛的影响.针刺研究, 1995. 20(3): p. 13-17.
    69. Bai, B., Wang, H., Liu, W.-Y., Song, C.-Y., Effect of anti-opioid peptide sera on the enhancement of electroacupuncture analgesia induced by neurotensin in PAG of rats. Acta Physiol. Sin, 1999. 51: p. 224-228.
    70. Yang, J. and B.C. Lin, Hypothalamic paraventricular nucleus plays a role in acupuncture analgesia through the central nervous system in the rat. Acupunct Electrother Res, 1992. 17(3): p. 209-20.
    71. Yang, J., et al., [Effects of stimulation and cauterization of hypothalamic paraventricular nucleus on acupuncture analgesia]. Sheng Li Xue Bao, 1992. 44(5): p. 455-60.
    72. Yang, J., et al., Through central arginine vasopressin, not oxytocin and endogenous opiate peptides, glutamate sodium induces hypothalamic paraventricular nucleus enhancing acupuncture analgesia in the rat. Neurosci Res, 2006. 54(1): p. 49-56.
    73. Yang, J., et al., Only arginine vasopressin, not oxytocin and endogenous opiate peptides, in hypothalamic paraventricular nucleus play a role in acupuncture analgesia in the rat. Brain Res Bull, 2006. 68(6): p. 453-8.
    74. Liu, C., et al., [Role of adenosine in weak electro-acupuncture-induced depression of nociceptive response of spinal dorsal horn neurons in rats]. Zhen Ci Yan Jiu, 1994. 19(2): p. 52-5.
    75. Liu, C., F. Zhao, and L. Zhu, [Involvement of purines in analgesia produced by weak electro-acupuncture]. Zhen Ci Yan Jiu, 1994. 19(1): p. 59-62, 54.
    76. Yang, J., et al., Central oxytocin enhances antinociception in the rat. Peptides, 2007. 28(5): p. 1113-9.
    77.刘文彦,宋.,杨俊,脊髓内催产素参与电针镇痛.针刺研究, 1990. 15(1): p. 24-29.
    78. Yang, J., et al., Effect of oxytocin on acupuncture analgesia in the rat. Neuropeptides, 2007. 41(5): p. 285-92.
    79. Faris, P.L., et al., Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia. Science, 1983. 219(4582): p. 310-2.
    80. Han, J.S., X.Z. Ding, and S.G. Fan, Cholecystokinin octapeptide (CCK-8): antagonism to electroacupuncture analgesia and a possible role in electroacupuncture tolerance. Pain, 1986. 27(1): p. 101-15.
    81. Liu, N.J., et al., Cholecystokinin octapeptide reverses the inhibitory effect induced by electroacupuncture on C-fiber evoked discharges. Int J Neurosci, 1996. 86(3-4): p. 241-7.
    82. Zhou, Y., et al., Increased release of immunoreactive CCK-8 by electroacupuncture and enhancement of electroacupuncture analgesia by CCK-B antagonist in rat spinal cord. Neuropeptides, 1993. 24(3): p. 139-44.
    83. Meunier, J.C., et al., Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature, 1995. 377(6549): p. 532-5.
    84. Reinscheid, R.K., et al., Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science, 1995. 270(5237): p. 792-4.
    85.张秀琳,朱崇斌,许绍苏,大鼠侧脑室及鞘内注射孤啡肽对痛反应及针刺镇痛的影响.生理学报, 1997. 49(5): p. 575-580.
    86. Tian, J.H., et al., Endogenous orphanin FQ: evidence for a role in the modulation of electroacupuncture analgesia and the development of tolerance to analgesia produced by morphine and electroacupuncture. Br J Pharmacol, 1998. 124(1): p. 21-6.