鞘内注射抗—脑源性神经营养因子对大鼠后足切割痛觉的影响
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摘要
研究背景目前关于脑源性神经生长因子(BDNF)在神经病理性疼痛和炎性疼痛中的作用研究广泛,已经初步证实BDNF是神经病理性疼痛和炎性疼痛的产生和维持中极为重要的神经递质。对于脊髓中BDNF水平的干预能起到减轻痛觉过敏的效果。然而当前对于BDNF在切割疼痛的产生维持以及切割后痛觉过敏等过程中扮演的角色仍知之甚少。而切割疼痛广泛存在于生活当中,人类深受其害,外科手术后的疼痛问题解决尚不够满意。这些都促使我们对切割疼痛的机理做更深入研究。本实验就是力图探究脊髓背角和背根神经节(DRG)中BDNF在切割疼痛发生中的作用。
方法在异氟醚麻醉下纵行切割大鼠后足,在手术后不同时段取脊髓和DRG观察脊髓背角和DRG中水平变化和表达定位。分别应用免疫荧光双重标记法和免疫组织化学方法检测BDNF水平。观察利多卡因坐骨神经阻滞后对脊髓背角和DRG内BDNF水平的影响。分别在切割前一小时鞘内和腹腔内注射抗BDNF血清,观察其对切割后足大鼠的行为学改变。
结果大鼠后足切割导致其同侧DRG和腰段脊髓BDNF水平上调,而胸段没有明显变化。脊髓中BDNF水平上调主要定位于神经元而不是星形胶质细胞或小胶质细胞。切割前应用局麻药利多卡因阻滞坐骨神经能够阻滞同侧DRG和腰段脊髓BDNF水平上调。鞘内注射抗BDNF血清能显著抑制切割引起的痛觉过敏。腹腔注射抗BDNF血清无上述效果。
结论上述研究表明,切割导致的同侧DRG和腰段脊髓背角中BDNF水平上调与躯体感觉传入神经功能密切相关。而增高的BDNF积极参与切割诱发的痛觉过敏。
Background: The pathogenic role of brain derived neurotrophic factor (BDNF) in the incisional pain is poorly understood. The present study explores the role of the BDNF in the incision-induced pain hypersensitivity.
Methods: A longitudinal incision was made in one plantar hind paw of isoflurane-anesthetized rats. Dorsal root ganglias (DRG) and spinal cords were removed at various postoperative times (1-72 h). Expression pattern of BDNF was determined by immunohistochemistry and double-labeling immunofluorescence. Lodocaine-induced blockade of sciatic nerve function was used to determine the importance of afferent nerve activity on BDNF expression in the DRG and spinal cord after incision. Anti-BDNF antibody was administered intrathecally (IT) or intraperitoneal (IP) to modulate the spinal BDNF or peripheral BDNF after incision.
Results: After hind-paw incision, the BDNF was upregulated in the ipsilateral lumbar DRG and spinal cord. Thoracic BDNF remained unchanged in response to incision. The upregulated spinal BDNF was mainly localized in the neurons but not microglia or astrocytes. Sciatic nerve blockade prevented the increase of BDNF in the DRG and spinal cord. IT injection of BDNF antibody greatly inhibited the mechanical allodynia induced by Incision whereas IP administration had only marginal effect.
Conclusions: The present study showed that incision induced the segmental upregulation of BDNF in the DRG and spinal cord through somatic afferent nerve transmission, and the upregulated BDNF contributed to the pain hypersentivity induced by surgical incision.
方法在异氟醚麻醉下纵行切割大鼠后足,在手术后不同时段取脊髓和DRG观察脊髓背角和DRG中水平变化和表达定位。分别应用免疫荧光双重标记法和免疫组织化学方法检测BDNF水平。观察利多卡因坐骨神经阻滞后对脊髓背角和DRG内BDNF水平的影响。分别在切割前一小时鞘内和腹腔内注射抗BDNF血清,观察其对切割后足大鼠的行为学改变。
结果大鼠后足切割导致其同侧DRG和腰段脊髓BDNF水平上调,而胸段没有明显变化。脊髓中BDNF水平上调主要定位于神经元而不是星形胶质细胞或小胶质细胞。切割前应用局麻药利多卡因阻滞坐骨神经能够阻滞同侧DRG和腰段脊髓BDNF水平上调。鞘内注射抗BDNF血清能显著抑制切割引起的痛觉过敏。腹腔注射抗BDNF血清无上述效果。
结论上述研究表明,切割导致的同侧DRG和腰段脊髓背角中BDNF水平上调与躯体感觉传入神经功能密切相关。而增高的BDNF积极参与切割诱发的痛觉过敏。
Background: The pathogenic role of brain derived neurotrophic factor (BDNF) in the incisional pain is poorly understood. The present study explores the role of the BDNF in the incision-induced pain hypersensitivity.
Methods: A longitudinal incision was made in one plantar hind paw of isoflurane-anesthetized rats. Dorsal root ganglias (DRG) and spinal cords were removed at various postoperative times (1-72 h). Expression pattern of BDNF was determined by immunohistochemistry and double-labeling immunofluorescence. Lodocaine-induced blockade of sciatic nerve function was used to determine the importance of afferent nerve activity on BDNF expression in the DRG and spinal cord after incision. Anti-BDNF antibody was administered intrathecally (IT) or intraperitoneal (IP) to modulate the spinal BDNF or peripheral BDNF after incision.
Results: After hind-paw incision, the BDNF was upregulated in the ipsilateral lumbar DRG and spinal cord. Thoracic BDNF remained unchanged in response to incision. The upregulated spinal BDNF was mainly localized in the neurons but not microglia or astrocytes. Sciatic nerve blockade prevented the increase of BDNF in the DRG and spinal cord. IT injection of BDNF antibody greatly inhibited the mechanical allodynia induced by Incision whereas IP administration had only marginal effect.
Conclusions: The present study showed that incision induced the segmental upregulation of BDNF in the DRG and spinal cord through somatic afferent nerve transmission, and the upregulated BDNF contributed to the pain hypersentivity induced by surgical incision.
引文
Bloechlinger S, Karchewski LA, Woolf CJ. Dynamic changes in glypican-1 expression in dorsal root ganglion neurons after peripheral and central axonal injury.Eur J Neurosci. 2004; 19:1119-32.
Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 1996; 64: 493-501.
Brennan TJ, Zahn PK, Pogatzki-Zahn EM: Mechanisms of incisional pain,Anesthesiology Clinics of North America. Edited by Joshi GP, Fleisher LA.Philadelphia, Saunders, 2005, pp 1-20
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53:55-63.
Cho HJ, Kim JK, Zhou XF, Rush RA. Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation Brain Res. 1997; 764:269-72.
Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW,De Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005,438:1017-21.
Dolan S, Kelly JG, Huan M, Nolan AM. Transient up-regulation of spinal cyclooxygenase-2 and neuronal nitric oxide synthase following surgical inflammation.Anesthesiology. 2003; 98:170-80.
Fu D, Guo Q, Ai Y, Cai H, Yan J, Dai R. Glial activation and segmental upregulation of interleukin-1beta (IL-1beta) in the rat spinal cord after surgical incision.Neurochem Res. 2006; 31:333-40.
Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, et al. Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J. Neurosci. 1999;19:5138-48
Kishino A, Nakayama C. Enhancement of BDNF and activated-ERK immunoreactivity in spinal motor neurons after peripheral administration of BDNF. Brain Res. 2003; 964: 56-66.
Kroin JS, Ling ZD, Buvanendran A, Tuman KJ. Upregulation of spinal cyclooxygenase-2 in rats after surgical incision. Anesthesiology 2004; 100: 364-9.
Luo XG, Rush RA, Zhou XF. Ultrastructural localization of brain-derived neurotrophic factor in rat primary sensory neurons. Neurosci. Res. 2001;39:377-84.
Matayoshi S, Jiang N, Katafuchi T, Koga K, Furue H, et al. Actions of brain-derived neurotrophic factor on spinal nociceptive transmission during inflammation in the rat.J. Physiol. 2005; 569:685-95.
Merighi A, Carmignoto G, Gobbo S, Lossi L, Salio C, et al. Neurotrophins in spinal cord nociceptive pathways. Prog. Brain Res. 2004; 146:291-321.
Michael GJ, Averill S, Nitkunan A, Rattray M, Bennett DL, et al. Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in trkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J.Neurosci. 1997;17:8476-90.
Miletic G, Hanson EN, Miletic V. Brain-derived neurotrophic factor-elicited or sciatic ligation-associated phosphorylation of cyclic AMP response element binding protein in the rat spinal dorsal horn is reduced by block of tyrosine kinase receptors.Neurosci.Lett.2004;361:269-71.
Myles PS, Power I. Clinical update: postoperative analgesia Lancet. 2007; 369:810-22
Onda A, Murata Y, Rydevik B, Larsson K, Kikuchi S, Olmarker K. Infliximab attenuates irnmunoreactivity of brain-derived neurotrophic factor in a rat model of herniated nucleus pulposus. Spine 2004; 29:1857-61.
Pezet S, Malcangio M, Lever IJ, Perkinton MS, Thompson SW, et al. Noxious stimulation induces trk receptor and downstream ERK phosphorylation in spinal dorsal horn. Mol. Cell Neurosci. 2002 21:684-95.
Pezet S, McMahon SB Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci. 2006; 29:507-38.
Thompson SW, Bennett DL, Kerr BJ, Bradbury EJ, McMahon SB.. Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc. Natl. Acad. Sci. USA 1999; 96:7714-18.
Yajima Y, Narita M, Narita M, Matsumoto N, Suzuki T.. Involvement of a spinal brainderived neurotrophic factor/full-length trkB pathway in the development of nerve injuryinduced thermal hyperalgesia in mice. Brain Res. 2002; 958:338-46.
Yaksh TL Analgetic actions of intrathecal opiates in cat and primate. Brain Res.1978; 153:205-10.
Yi XN, Zheng LF, Zhang JW, Zhang LZ, Xu YZ, Luo G, Luo XG. Dynamic changes in Robo2 and Slit1 expression in adult rat dorsal root ganglion and sciatic nerve after peripheral and central axonal injury Neurosci Res. 2006; 56:314-21.
Zahn PK, Brennan TJ. Lack of effect of intrathecally administered N-methyl-D-aspartate receptor antagonists in a rat model for postoperative pain.Anesthesiology 1998; 88: 143-156.
Zahn PK, Umali E, Brennan TJ. Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain. Pain 1998; 74: 213-223.
Zhu X, Conklin D, Eisenach JC Cyclooxygenase-1 in the spinal cord plays an important role in postoperative pain. Pain 2003;104:15-23.
1.于频 主编.系统解剖学(第四版).人民卫生出版社.北京,1996年。
2.韩济生关新民.医用神经生物学[M]。武汉:武汉出版社。1996年。
3.Mikito Kawamata.Effects of Length of Surgical Incision on Hyperexcitability in Spinal Dorsal Horn Neurons in the Rat.Anesthesiology 2003;99:A917。
4.Douglas W Wilmore,Frank Sawyer.Recent advances Management of patients in fast track surgery.British Medical Journal 2001;322:473-476
5.王尧 杜子威。神经生物化学和分子生物学[M]。北京:人民卫生出版社。1997
6.Xue-Jun Song,Carlos Vizcarra.Hyperalgesia and Neural Excitability Following Injuries to Central and Peripheral Branches of Axons and Somata of Dorsal Root Ganglion Neurons.J Neurophysiol,2003 89:2185-2193
7.Liu,X.-G.,Eschenfelder,S.,Habler,H.-J.and Janig,W.(2000)Spontaneous activity of axotomized neurons after L5 spinal nerve injury in rats.Pain,84:309-318.
8.WD Willis,Ann N Y.Role of neurotransmitters in sensitization of pain responses.Acad Sci(2001)933:142-56.
9.Kawamata,Mikito;Narimatsu,Eichi;Kozuka,Yuji etl Effects of Halothane and Isoflurane on Hyperexcitability of Spinal Dorsal Horn Neurons after Incision in the Rat[J]Pain and Regional Anesthesia.Volume 102(1),January 2005,pp 165-174
10.信文君,黎明涛,刘先国.磷酸化CaMKII在脊髓背角C.纤维诱发LTP诱导和维持中的作用。生理学报,56(1):83-89。
11.Azkue JJ,Liu XG,Zimmermann M,Sandkuhler J(2003)Induction of long-term potentiation of C fibre-evoked spinal field potentials requires recruitment of group Ⅰ,but not group Ⅱ/Ⅲ metabotropic glutamate receptors.Pain 106:373-379.
12.鞠躬,吕国蔚,等.神经生物学[M].北京:人民卫生出版社,2004年
13.Haibin Wang etl。Bradykinin Produces Pain Hypersensitivity by Potentiating Spinal Cord Glutamatergic Synaptic Transmission o The Journal of Neuroscience,August 31,2005,25(35):7986-7992。
14.高崇荣,王家双.神经性疼痛诊疗学[M].郑州:郑州大学出版社.2006年
15.T Yamamoto Masuio N-methyl-D-aspartate(NMDA)receptor and pain.(1996)45:1312-1318
16.Lee HJ;Brennan TJ o The effect of the AMPA/kainate receptor antagonist LY293558 in a rat model of postoperative pain.JOURNAL OF PAIN 7(10):768-777 OCT 2006.
17.E M Pogatzki-Zahn,JS Niemeier,LS Sorkino Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision.,(2006)20:245-53:
18.Ji-Tian Xu,Wen-Jun Xian-Guo Liu.The role of tumour necrosis factor-alpha in the neuropathic pain produced by lumbar 5 ventral root transection in rat.Pain,123:306-321.
19.Keiichi Omote,Tomoyuki Kawamatao The Effects of Peripheral Administration of a Novel Selective Antagonist for Prostaglandin E Receptor Subtype EP_1,ONO-8711,in a Rat Model of Postoperative Pain.Anesth Analg 2001;92:233-238.
20.胡兴国 张云翔 曾因明。鞘内吗啡对切口疼痛模型大鼠脊髓背角P物质的影响。中华麻醉学杂志2001年11月第21卷第11期。
21.McLeod AL,Ritchie J,Cuello AC,et al.Upregulation of an opioid-mediated antinociceptive mechanism in transgenic mice over-expressing substance P in the spinal cord.Neuroscience,2000。
22.舒斯云 包新民.神经元:细胞和分子生物学[M].北京:科学出版社.2001年
23.刘成龙,靳安民,等.大鼠脊髓损伤后一氧化氮全酶基因表达的变化[J].中华实验外科杂志,2001,1,1,18(1):74-75.
24.于洪波 莫宁 戴体俊。氯胺酮对大鼠交感神经节NO与NOS的抑制作用。科研课题。2006年,第2卷。第04期(半月刊)。
25.david Clark etl。Blockade of the Complement C5a Receptor Reduces Incisional Allodynia,Edema,and Cytokine Expression;J Anesthesiology 2006;104:1274-1282
26.Di FU etl;Glial Activation and Segmental Upregulation of Interlukin-1β(IL-1β)in the Rat Spinal cord after Surgical Incision.Neurochem Res(2006)31:333-340
27.Oddiah,Daniela;Anand,Praveen o Rapid increase of NGF,BDNF and NT-3mRNAs in inflamed bladder。Volume 9(7),11 May 1998,p 1455-1458。
28.Wu,Chaoran.Nerve growth factor expression after plantar incision in the rat.Anesthesiology 107(1):128-35 2007 Jul.
29.Cho HJ,Kim SY,Park MJ,et alo Expression of mRNA for brain-derived neurotrophic factor in the dorsal root ganglion following peripheral inflammationl Brain Res,1997,749:35823621.
30.Dougherty KD,Dreyfus C F,Black IB.Brain2derived neurotrophic factor in astrocytes,oligodendrocyte,and microglia/macrophages after spinal cord injury [J].Neurobiol Dis,2000,7(6):574 - 585.
31.BamberN I,L i H,Lu X,et al.Neurotrophins BDNF and NT23 promote axonal re2entry into the distal host spinal cord through Schwann cell2seeded mini2channels[J].Eur J Neurosci,2001,13:257 - 268.
32.Hee-Jung Cho,Jeong-Ki Kim a,Xin-Fu Zhou.Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation;RushBrain Research 764_1997.269-272;
33.余科炜 叶晓健;脑源性神经营养因子基因修饰细胞移植治疗大鼠脊髓损伤的电生理研究;中华外科杂志2001年9月第39卷第9期;
34.Zhao,et al。Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic painJing.Cell.Neurosci.31(2006)539-548
35.何农。N-甲基-D-天门冬氨酸-一氧化氮系统在脊髓痛觉过敏机制中作用的实验研究.中国协和医科大学;中国医学科学院博士学位论文
36.Yang HW,Hu XD,Zhang HM,Xin WJ,Li MT,Zhang T,Zhou LJ,Liu XG(2004)The roles of CAMKII,PKA and PKC in the induction and maintenance of LTP of c-fiber evoked field potentials in rat spinal dorsal hom.J Neurophysiol,91(3):1122-1133.
37.现代神经科学研究方法。吴俊芳主编。中国协和医科大学出版社。2006年北京
Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 1996; 64: 493-501.
Brennan TJ, Zahn PK, Pogatzki-Zahn EM: Mechanisms of incisional pain,Anesthesiology Clinics of North America. Edited by Joshi GP, Fleisher LA.Philadelphia, Saunders, 2005, pp 1-20
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53:55-63.
Cho HJ, Kim JK, Zhou XF, Rush RA. Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation Brain Res. 1997; 764:269-72.
Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW,De Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005,438:1017-21.
Dolan S, Kelly JG, Huan M, Nolan AM. Transient up-regulation of spinal cyclooxygenase-2 and neuronal nitric oxide synthase following surgical inflammation.Anesthesiology. 2003; 98:170-80.
Fu D, Guo Q, Ai Y, Cai H, Yan J, Dai R. Glial activation and segmental upregulation of interleukin-1beta (IL-1beta) in the rat spinal cord after surgical incision.Neurochem Res. 2006; 31:333-40.
Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, et al. Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J. Neurosci. 1999;19:5138-48
Kishino A, Nakayama C. Enhancement of BDNF and activated-ERK immunoreactivity in spinal motor neurons after peripheral administration of BDNF. Brain Res. 2003; 964: 56-66.
Kroin JS, Ling ZD, Buvanendran A, Tuman KJ. Upregulation of spinal cyclooxygenase-2 in rats after surgical incision. Anesthesiology 2004; 100: 364-9.
Luo XG, Rush RA, Zhou XF. Ultrastructural localization of brain-derived neurotrophic factor in rat primary sensory neurons. Neurosci. Res. 2001;39:377-84.
Matayoshi S, Jiang N, Katafuchi T, Koga K, Furue H, et al. Actions of brain-derived neurotrophic factor on spinal nociceptive transmission during inflammation in the rat.J. Physiol. 2005; 569:685-95.
Merighi A, Carmignoto G, Gobbo S, Lossi L, Salio C, et al. Neurotrophins in spinal cord nociceptive pathways. Prog. Brain Res. 2004; 146:291-321.
Michael GJ, Averill S, Nitkunan A, Rattray M, Bennett DL, et al. Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in trkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J.Neurosci. 1997;17:8476-90.
Miletic G, Hanson EN, Miletic V. Brain-derived neurotrophic factor-elicited or sciatic ligation-associated phosphorylation of cyclic AMP response element binding protein in the rat spinal dorsal horn is reduced by block of tyrosine kinase receptors.Neurosci.Lett.2004;361:269-71.
Myles PS, Power I. Clinical update: postoperative analgesia Lancet. 2007; 369:810-22
Onda A, Murata Y, Rydevik B, Larsson K, Kikuchi S, Olmarker K. Infliximab attenuates irnmunoreactivity of brain-derived neurotrophic factor in a rat model of herniated nucleus pulposus. Spine 2004; 29:1857-61.
Pezet S, Malcangio M, Lever IJ, Perkinton MS, Thompson SW, et al. Noxious stimulation induces trk receptor and downstream ERK phosphorylation in spinal dorsal horn. Mol. Cell Neurosci. 2002 21:684-95.
Pezet S, McMahon SB Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci. 2006; 29:507-38.
Thompson SW, Bennett DL, Kerr BJ, Bradbury EJ, McMahon SB.. Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc. Natl. Acad. Sci. USA 1999; 96:7714-18.
Yajima Y, Narita M, Narita M, Matsumoto N, Suzuki T.. Involvement of a spinal brainderived neurotrophic factor/full-length trkB pathway in the development of nerve injuryinduced thermal hyperalgesia in mice. Brain Res. 2002; 958:338-46.
Yaksh TL Analgetic actions of intrathecal opiates in cat and primate. Brain Res.1978; 153:205-10.
Yi XN, Zheng LF, Zhang JW, Zhang LZ, Xu YZ, Luo G, Luo XG. Dynamic changes in Robo2 and Slit1 expression in adult rat dorsal root ganglion and sciatic nerve after peripheral and central axonal injury Neurosci Res. 2006; 56:314-21.
Zahn PK, Brennan TJ. Lack of effect of intrathecally administered N-methyl-D-aspartate receptor antagonists in a rat model for postoperative pain.Anesthesiology 1998; 88: 143-156.
Zahn PK, Umali E, Brennan TJ. Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain. Pain 1998; 74: 213-223.
Zhu X, Conklin D, Eisenach JC Cyclooxygenase-1 in the spinal cord plays an important role in postoperative pain. Pain 2003;104:15-23.
1.于频 主编.系统解剖学(第四版).人民卫生出版社.北京,1996年。
2.韩济生关新民.医用神经生物学[M]。武汉:武汉出版社。1996年。
3.Mikito Kawamata.Effects of Length of Surgical Incision on Hyperexcitability in Spinal Dorsal Horn Neurons in the Rat.Anesthesiology 2003;99:A917。
4.Douglas W Wilmore,Frank Sawyer.Recent advances Management of patients in fast track surgery.British Medical Journal 2001;322:473-476
5.王尧 杜子威。神经生物化学和分子生物学[M]。北京:人民卫生出版社。1997
6.Xue-Jun Song,Carlos Vizcarra.Hyperalgesia and Neural Excitability Following Injuries to Central and Peripheral Branches of Axons and Somata of Dorsal Root Ganglion Neurons.J Neurophysiol,2003 89:2185-2193
7.Liu,X.-G.,Eschenfelder,S.,Habler,H.-J.and Janig,W.(2000)Spontaneous activity of axotomized neurons after L5 spinal nerve injury in rats.Pain,84:309-318.
8.WD Willis,Ann N Y.Role of neurotransmitters in sensitization of pain responses.Acad Sci(2001)933:142-56.
9.Kawamata,Mikito;Narimatsu,Eichi;Kozuka,Yuji etl Effects of Halothane and Isoflurane on Hyperexcitability of Spinal Dorsal Horn Neurons after Incision in the Rat[J]Pain and Regional Anesthesia.Volume 102(1),January 2005,pp 165-174
10.信文君,黎明涛,刘先国.磷酸化CaMKII在脊髓背角C.纤维诱发LTP诱导和维持中的作用。生理学报,56(1):83-89。
11.Azkue JJ,Liu XG,Zimmermann M,Sandkuhler J(2003)Induction of long-term potentiation of C fibre-evoked spinal field potentials requires recruitment of group Ⅰ,but not group Ⅱ/Ⅲ metabotropic glutamate receptors.Pain 106:373-379.
12.鞠躬,吕国蔚,等.神经生物学[M].北京:人民卫生出版社,2004年
13.Haibin Wang etl。Bradykinin Produces Pain Hypersensitivity by Potentiating Spinal Cord Glutamatergic Synaptic Transmission o The Journal of Neuroscience,August 31,2005,25(35):7986-7992。
14.高崇荣,王家双.神经性疼痛诊疗学[M].郑州:郑州大学出版社.2006年
15.T Yamamoto Masuio N-methyl-D-aspartate(NMDA)receptor and pain.(1996)45:1312-1318
16.Lee HJ;Brennan TJ o The effect of the AMPA/kainate receptor antagonist LY293558 in a rat model of postoperative pain.JOURNAL OF PAIN 7(10):768-777 OCT 2006.
17.E M Pogatzki-Zahn,JS Niemeier,LS Sorkino Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision.,(2006)20:245-53:
18.Ji-Tian Xu,Wen-Jun Xian-Guo Liu.The role of tumour necrosis factor-alpha in the neuropathic pain produced by lumbar 5 ventral root transection in rat.Pain,123:306-321.
19.Keiichi Omote,Tomoyuki Kawamatao The Effects of Peripheral Administration of a Novel Selective Antagonist for Prostaglandin E Receptor Subtype EP_1,ONO-8711,in a Rat Model of Postoperative Pain.Anesth Analg 2001;92:233-238.
20.胡兴国 张云翔 曾因明。鞘内吗啡对切口疼痛模型大鼠脊髓背角P物质的影响。中华麻醉学杂志2001年11月第21卷第11期。
21.McLeod AL,Ritchie J,Cuello AC,et al.Upregulation of an opioid-mediated antinociceptive mechanism in transgenic mice over-expressing substance P in the spinal cord.Neuroscience,2000。
22.舒斯云 包新民.神经元:细胞和分子生物学[M].北京:科学出版社.2001年
23.刘成龙,靳安民,等.大鼠脊髓损伤后一氧化氮全酶基因表达的变化[J].中华实验外科杂志,2001,1,1,18(1):74-75.
24.于洪波 莫宁 戴体俊。氯胺酮对大鼠交感神经节NO与NOS的抑制作用。科研课题。2006年,第2卷。第04期(半月刊)。
25.david Clark etl。Blockade of the Complement C5a Receptor Reduces Incisional Allodynia,Edema,and Cytokine Expression;J Anesthesiology 2006;104:1274-1282
26.Di FU etl;Glial Activation and Segmental Upregulation of Interlukin-1β(IL-1β)in the Rat Spinal cord after Surgical Incision.Neurochem Res(2006)31:333-340
27.Oddiah,Daniela;Anand,Praveen o Rapid increase of NGF,BDNF and NT-3mRNAs in inflamed bladder。Volume 9(7),11 May 1998,p 1455-1458。
28.Wu,Chaoran.Nerve growth factor expression after plantar incision in the rat.Anesthesiology 107(1):128-35 2007 Jul.
29.Cho HJ,Kim SY,Park MJ,et alo Expression of mRNA for brain-derived neurotrophic factor in the dorsal root ganglion following peripheral inflammationl Brain Res,1997,749:35823621.
30.Dougherty KD,Dreyfus C F,Black IB.Brain2derived neurotrophic factor in astrocytes,oligodendrocyte,and microglia/macrophages after spinal cord injury [J].Neurobiol Dis,2000,7(6):574 - 585.
31.BamberN I,L i H,Lu X,et al.Neurotrophins BDNF and NT23 promote axonal re2entry into the distal host spinal cord through Schwann cell2seeded mini2channels[J].Eur J Neurosci,2001,13:257 - 268.
32.Hee-Jung Cho,Jeong-Ki Kim a,Xin-Fu Zhou.Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation;RushBrain Research 764_1997.269-272;
33.余科炜 叶晓健;脑源性神经营养因子基因修饰细胞移植治疗大鼠脊髓损伤的电生理研究;中华外科杂志2001年9月第39卷第9期;
34.Zhao,et al。Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic painJing.Cell.Neurosci.31(2006)539-548
35.何农。N-甲基-D-天门冬氨酸-一氧化氮系统在脊髓痛觉过敏机制中作用的实验研究.中国协和医科大学;中国医学科学院博士学位论文
36.Yang HW,Hu XD,Zhang HM,Xin WJ,Li MT,Zhang T,Zhou LJ,Liu XG(2004)The roles of CAMKII,PKA and PKC in the induction and maintenance of LTP of c-fiber evoked field potentials in rat spinal dorsal hom.J Neurophysiol,91(3):1122-1133.
37.现代神经科学研究方法。吴俊芳主编。中国协和医科大学出版社。2006年北京