摘要
感觉神经元特异性受体(sensory neuron-specific receptor,SNSR)SNSR的mRNA只独特地存在于脊髓背根神经节和三叉神经节的中小型神经元里,具有高度的组织特异性,该类神经元为伤害性信息传入的初级神经元,推测SNSR可能参与伤害性信息的调制。本实验应用SNSR受体的激动剂(BAM8-22,MSH)通过行为学、免疫组织化学等实验方法,研究SNSR受体在CFA慢性炎症痛大鼠脊髓背角和背根神经节痛觉调制中的作用。
行为学实验结果表明:鞘内注射SNSR受体激动剂(BAM8-22,MSH)能剂量依赖地恢复CFA炎性大鼠热刺激缩脚反射潜伏期,降低热痛觉过敏,减轻足跖炎性红肿程度。免疫组织化学结果显示:鞘内注射BAM8-22能下调大鼠CFA炎症侧脊髓背角和背根神经节NOS,nNOS和CGRP阳性细胞表达量,从细胞水平阐明SNSR受体在炎症痛模型中痛觉传递和调制的作用。
我们的研究证实SNSR受体参与了以DRG为代表的脊髓水平的痛觉调制,探讨SNSR受体在炎性痛中的作用及其与其它兴奋性神经递质之间的关系,有助于人们加深对疼痛机制的认识,也可为临床镇痛和新型镇痛药的开发提供依据。
The mRNA of sensory neuron-specific receptor is uniquely located in the small diameter neurons in dorsal root ganglia(DRG) and trigeminal ganglia(TG).Because these neurons are the primary nociceptive sensory neuron,the physiological effect of SNSR may modulate the transfer of nociceptive signal.This study was conducted with behavioral and immunohistochemistry techniques application of SNSR ligands;Bovine adrenal medulla 8-22(BAM8-22) and Tyr6-γ2-MSH-6-12 to research the pain regulation of SNSR in the level of spinal cord dorsal horn and dorsal root ganglion.
In behavioral experiment,i.t.(intrathecal injection) administration of SNSR agonists-BAM8-22 and Tyr6-γ2-MSH-6-12 recovery paw withdrawal latency by thermal stimulation,weaken the thermal hyperalgesia induced by i.pl.injection of complete Freund's adjuvant(CFA),ease paw inflammation swell.The immunohistochemical result is that i.t.administration of BAM8-22 lead to decrease the positive neurons expression of NOS,nNOS and CGRP in spinal cord dorsal horn and DRG,which illustrate SNSR function in pain transference and regulation from cellular mechanisms in CFA-treated rats.
The present study demonstrates that SNSR modulate the transfer of nociceptive signal.A better understanding of the mechanisms underlying the SNSR-induced the antihyperalgesic effects in chronic inflammation will be pivotal in the development of SNSR-targeted medication for the treatment of chronic pain.
引文
1.赵志奇主编.疼痛及其脊髓机理[M].上海:上海科技教育出版社,2000:1-2.
2.Block BM,Hurley RW,Raja SN.Mechanism-based therapies for pain[J].Drug News Perspect.2004,17(3):172-86.
3.王福根.疼痛研究进展[J].中华医学信息导报,2004,22:21.
4.Michel P,Alice M,Michel H,et al.Gene Therapy of Chronic Pain[J].Current Gene Therapy.2003,3:223-238.
5.Scholz J,Woolf CJ,Can we conquer pain[J]? Nat.Neurosci.2002,5:1062-1067.
6.Woolf CJ.Pain[J].Neurobiol Dis.2000,7(5):504-10.
7.Narabayashi M,Saijo Y,Takenoshita S,et al.Opioid rotation from oral morphine to oral oxycodone in cancer patients with intolerable adverse effects:an open-label trial [J].Jpn J Clin Oncol,2008,38:296-304
8.Terman GW,Bonica JJ.Spinal mechanisms and their modulation[J].Bonica's Management of Pain,2001,3:73-152.
9.Tillman DB,Treede RD,Meyer RA,et al.Response of C fibre nociceptors in the anaesthetized monkey to heat stimuli:correlation with pain threshold in humans[J].J physiol,1995,485(3):767-774.
10.Jancso G,Kiraly F,Jancso-Gabor A.Pharmacologically induced selective degeneration of chemosensitive primary sensory neurons[J].Nature,1996,270:741-743.
11.Lembech F,Donnerer J.The wide spectrum of function of capsaicin-sensitive nociceptive afferents[J].Advances in pain research and therapy,1992,45-53.
12.Ren K.Primary afferents and inflammatory hyperexcitability[J].Pain,1996,67:1-2.
13.Torebjork HK.Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans[J].J Physiol,1992,448:765-780.
14.Snider WD,McMahon SB.Tackling pain at the source:new ideas about nociceptors [J].Neuron,1998,20:629-632.
15.唐占英,王拥军等.不同大小背根节(DRG)神经元在痛觉调制中的作用[J].脊柱外科杂志,2005,3(2):115-117.
16.Millan MJ.The induction of pain:an integrative review[J].Prog.Neurobiol.1999,57:1-164.
17.Stucky CL,Lewin GR.Isolectin B(4)-positive and-negative nociceptors are functionally distinct[J].Neurosci,1999,19:6497-6505.
18.Ma W,Chabot JG,Powell KJ,et al.Localization and modulation of calcitonin gene related peptide-receptor component proteinimmunoreactive cells in the rat central and peripheral nervous systems[J].Neuroscience,2003,120(3):677-694.
19.Landry M,Aman K,Dostrovsky J,et al.Galanin expression in adult human dorsal root ganglion neurons:initial observations[J].Neuroscience,2003,117(4):795-809.
20.Caterina MJ,Julius D,Sense and specificity:a molecular identity for nocicepters[J].Current opinion in Neurobiology,1999,9:525-530.
21.Julius D,Basbaum AI.Molecular mechanisms of nociception[J],Nature,2001,413(6852):203-210.
22.Brooks J,Tracey I.From nociception to pain perception:imaging the spinal and supraspinal pathways[J].J Anat,2005,1:19-33.
23.McCleskey EW,Gold MS.Ion channels of nociception[J].Annu Rev Physiol,1999,61:835-856.
24.Mio K,Kubo Y,Ogura T,et al.Visualization of the trimeric P2X2 receptor with a crowncapped extracellular domain[J].Biochem Biophys Res Commun,2005,337:998-1005.
25.Gerevich Z,Muller C,Illes P.Metabotropic P2Y1 receptors inhibit P2X3 receptorchannels in rat dorsal root ganglion neurons[J].European Journal of Pharmacology,2005,521(1-3):34-38.
26.Gu JG,MacDermott AB.Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses[J].Nature,1997,389:749-753.
27.Chen CC,Akopian AN,Sivilotti L,et al.A P2X purinoceptor expressed by a subset of sensory neurons[J].Nature,1995,377:428-431.
28.Boehm S.ATP stimulates sympathetic transmitter release via presynaptic P2X purinoceptors [J]. J Neurosci, 1999,19: 737-746.
29. Gu JG, MacDermott AB. Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses [J]. Nature, 1997,389: 749-753.
30. Vulchanova L, Riedl MS, Buell G, et al. Immunohistochemical study of the P2X2 and P2X3 receptor subunits in rat and monkey sensory neurons and their central terminals [J]. Neuropharmacology, 1997, 36: 1229-1242.
31. Nakatsuka T, Tsuzuki K, Ling JX, et al. Distinct roles of P2X receptors in modulating glutamate release at different primary sensory synapses in rat spinal cord [J]. J Neurophysiol, 2003, 89: 3243-3252.
32. Hilliges M, Weidner C, Schmelz M, et al. ATP responses in human C nociceptors [J]. Pain, 2002,98: 59-68.
33. Hamilton SG, McMahon SB, Lewin GR. Selective activation of nociceptors by P2X receptor agonists in normal and inflamed rat skin [J]. J Physiol, 2001, 534: 437-445.
34. Dowd E, Mcqueen DS, Chessell IP, et al. P2X receptor-mediated excitation of nociceptive afferents in the normal and arthritic rat knee joint [J]. Br J Pharmacol, 1998,125: 341-346.
35. Guo A, Wang J, Li X, et al. Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites [J]. Eur J Neurosci, 1999,11: 946-958.
36. Tsuda M, Ueno S, Inoue K. Evidence for the involvement of spinal endogenous ATP and P2X receptors in nociceptive responses caused by formalin and capsaicin in mice [J]. Br. J. Pharmacol. 1999, 128: 1497-1504.
37. Barclay J, Patel S, Dom G. Functional down regulaton of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain [J]. J Neurosci, 2002, 22(18): 8139-8147.
38. Honore P, Kage K, Mikusa J, et al. Analgesic profile of intrathecal P2X3 antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats [J]. Pain, 2002, 99: 11-19.
39. Alan R. Molecular Physiology of P2X Receptors [J]. Physiol Rev, 2002, 82: 1013-1067.
40. Caterina Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway [J]. Nature, 1997, 398: 816-824.
41. Lon AB, Anthory JK, Williom CG, et al. Vanillod receptor expression suggests a sensory role for urinary bladdec cpithclial cells [J]. Proc Natl Acad Sct USA, 2001, 98:13396-13401.
42. Bevan S, Szolcsanyi J. Sensory neuron-specific actions of capsaicin: mechanisms and applications [J]. Trends in Neurosci, 1990, 11: 330-333.
43. Tiruppathi C, Ahmmed GU, Vogel SM, et al. Ca2+ signaling TRP channels and endothelial permeability [J]. Microcirculation, 2006,13: 693-708.
44. Szallasi A. Blumberg PM. Vanilloid (Capsaicin) receptors and mechanisms [J]. Pharmacol. Rev, 1999, 51: 159-212.
45. Nakagawa H, Hiura A. Capsaicin transient receptor potential (TRP) protein subfamilies and the particular relationship between capsaicin receptors and small primary sensory neurons [J]. Anat Sci Int, 2006, 81(3): 135-155
46. Caterina MJ, Schumacher MA, Tomingaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway [J]. Nature, 1997, 398: 816-824.
47. Michael GJ, Priestly JV. Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregulation by axotomy [J]. JNeurosci, 1999,19:1844-1854.
48. Ma QP. Expression of capsaicin receptor (VRl) by myelinated primary afferent neurons in rats [J]. Neurosci Lett, 2002, 319: 87-90.
49. Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli [J]. Neuron, 1998, 21: 531-543.
50. Jordt SE, Tominaga M, Julius D. Acid potentiation of the capsaicin receptor determined by a key extracellular site [J]. Proc. Natl. Acad. Sci. U.S.A, 2000, 97: 8134-8139
51. John BD, Julie G, Martin J, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia [J]. Nature, 2000, 405: 183-187.
52. Bolcskei K, Helyes Z, Szabo A, et al. Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using gene-deficient mice [J]. Pain, 2005, 117(3): 368-376.
53. Caterina MJ, Leffler A, Malmberg AB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor [J]. Science, 2000, 288 (5464): 306-313.
54. Davis JB, Gray J, Gunthorpe MJ, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia [J]. Nature, 2000, 405(6783): 183-187. 55. Ji RR, Samad TA, Jin SX, et al. p38MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia [J]. Neuron, 2002, 36: 57-68.
56. Hudson LJ, Bevan S, Wotherspoon G, Gentry C, et al. VR1 protein expression increases in undamaged DRG neurons after partial nerve injury [J]. Eur J Neurosci, 2001, 13(11): 2105-2114.
57. Tominaga M, Wada M, Masu M. Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia [J]. Proc. Natl. Acad. Sci. U. S. A, 2001,98: 6951-6956.
58. Lembo PM, Grazzini E, Groblewski T, O'Donnell D, Roy MO, Zhang J, Hoffert C, Cao J, Schmidt R, Pelletier M, Labarre M, Gosselin M, Fortin Y, Banville D, Shen SH, Strom P, Payza K, Dray A, Walker P, Ahmad S. Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs [J]. Nat Neurosci, 2002, 5: 201-209.
59. Mark J, Zylka, Xinzhong Dong, et al. Atypical expansion in mice of the sensory neuronspecific MrgG protein-coupled receptor family [J]. PNAS, 2003, 100: 10043-10048.
60. Hong Y, Dai P, Jiang J, Zeng X. Dual effects of intrathecal BAM22 on nociceptive responses in acute and persistent pain-potential function of a novel receptor [J]. Br J Pharmacol, 2004, 141: 423-430.
61. Grazzini E, Puma C, Roy MO, Yu XH, O'Donnell D, Schmidt R,Dautrey S, Ducharme J, Perkins M, Panetta R, Laird JM, Ahmad S, Lembo PM. Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats [J]. Proc Natl Acad Sci U S A, 2004, 101: 7175-7180.
62. Hager UA, Hein A, Lennerz JK, Zimmermann K, Neuhuber WL, Reeh PW. Morphological characterization of rat Mas-related G-protein-coupled receptor C and functional analysis of agonists[J].Neuroscience,2008,151:242-254.
63.Caterina MJ.Julius D.Sense and specificity:a molecular identity for nociceptors[J].Curr.Opin.Neurobiol,1999,9:525-530.
64.Frederic Simonin Brigitte L.Kieffer.Two faces for an opioid peptide and more receptors for pain research[J].Nature neuroscience,2002,5(3):185-186.
65.Maderdrut JL,Merchenthaler I,Sundberg DK,et al.Distribution and development of proenkephalin-like immunoreactivity in the lumbar spinal cord of the chicken[J].Brain Res,1986,377:29-40.
66.Garzon J,Hollt V,Lee,NM.et al.Endogenous opioid peptides:comparative evaluation of their receptor affinities in the mouse brain[J].Life Sci.,1983,33:291-294.
67.Quirion R.Weiss AS.Peptide E and other proenkephalin-derived peptides are potent kappa opiate receptor agonists[J].Peptides,1983,4:445-449.
68.Boersma CJ,Pool CW,et al.Characterization of opioid binding sites in the neural and intermediate lobe of the rat pituitary gland by quantitative receptor autoradiography [J].J.Neuroendocrinol,1994,6:47-56.
69.Nordlund JJ.α-melanocyte stimulating hormone:a ubiquitous cytokine with pigmenting effects[J].JAMA,1991,266(19):2753-2754.
70.Thody AJ,Ridley K,Penny RJ,et al.MSH are present in mammalian skin[J].Peptides,1983,4(6):813-816.
71.Chen T,Cai QY,Hong Y.Intrathecal sensory neuron-specific receptor agonists Bovine Adrenal Medulla 8-22 And(Tyr6)-2-MSH-6-12 inhibit formalin-evoked nociception and neuronal Fos-like immunoreactivity in the spinal cord of the rat[J].Neuroscience,2006,141:965-975.
72.韩济生主编.神经生理学纲要[M].北京:北京医科大学中国协和医科大学联合出版社,1999:706-727.
73.魏峰.脊髓背角痛觉传递和调制的一些化学解剖学观察[J].生理学进展,1996,27:327.
74.Watanabe H,Nakayama D,YuhkiM.Differential inhibitory effects of mu-opioids on substance P and capsaicin induced nociceptive behavior in mice [J]. Peptides, 2006, 27(4): 760-768.
75. Block BM, Hurley RW, Raja SN. Mechanism-based therapies for pain [J]. Drug News Perspect, 2004,17(3): 172-86.
76. Li YH, Han TZ, KMeng. Tonic facilitation of glutamate release by glycine binding sites on presynaptic NR2B-containing NMDA autoreceptors in the rat visual cortex [J] .Neuroscience Letters, 2008, 432(3): 212-216.
77. Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits : diversity , development and disease [J]. Curr Opin Neurobiol, 2001,11(3): 327-335.
78. McBam CJ, Mayer ML. N-methyl-D-aspartic acid receptor structure and function [J]. Physiol Rev, 1994, 74(3): 723-760.
79. Dingledine R, Borges K, Bowie D, et al. The glutamate receptor ion channels [J] . Pharmacol Rev, 1999, 51:7-61.
80. Karadottir R, Cavelier P, Bergersen LH, et al. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia [J]. Nature, 2005,438: 1162-1166.
81. Salter M, Fern R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury [J]. Nature, 2005,438: 1167-1171.
82. Gaunitz C, Schuttler A, Gillen C, et al. Formalin-induced changes of NMDA receptor subunit expression in the spinal cord of the rat [J]. Amino Acids, 2002, 23(123): 177-182.
83. Nagy GG, Watanabe M, Fukaya M, et al. Synapticdist ribution of the NR1, NR2A and NR2B subunits of the N-methyl-D-aspartate receptor in the rat lumbar spinal cord revealed with an antigen-unmasking technique [J]. Eur J Neurosci, 2004, 20(12): 3301-3312.
84. Momiyama A. Distinct synaptic and extrasynaptic NMDA receptors identified in dorsal horn neurones of the adult ratspinal cord [J]. J Physiol, 2000, 52(3): 621-628.
85. Pierre Paoletti, Jacques Neyton. NMDA receptor subunits: function and pharmacology [J]. Current Opinion in Pharmacology, 2007, 7: 39-47.
86. Chen NS, Li B, Murphy TH, et al. Site within N-methyl-D-aspartate receptor pore modulates channel gating. MolPharmacol [J]. 2004, 65(1): 157-164.
87. Wayne E Childers Jr, Reinhardt B Baudy. N-Methyl-D-Aspartate Antagonists and Neuropathic Pain: The Search for Relief [J]. Journal of Medicinal Chemistry, 2007, 50:2557-2562.
88. Benrath J, Brechtel C, Stark J, et al. Low dose of ketamine prevents long-term potentiation in pain pathways under strong opioid analgesia in the rat spinal cord in vivo [J]. Br.J.Anaesth, 2005, 95: 518-523.
89. Kosai K, Tateyama S, Ikeda T, et al. MK-801 reduces non-noxious stimulus-evoked Fos-like immunoreactivity in the spinal cord of rats with chronic constriction nerve injury [J]. Brain Res, 2001, 910: 12-18.
90. Martin HA, Arendt-Nielsen L. Effect of muscle pain and intrathecal AP-5 on electromyographic patterns during treadmill walking in the rat. Prog [J]. Neuropsychopharmacol. Biol. Psychiatry, 2000,24(7): 1151-1175.
91. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states [J]. Pain, 1991,44: 293-299.
92. Sotgiu ML, Biella G. Differential effects of MK-801, a N-methyl-D-aspartate Non-competitive antagonist on the dorsal horn neuron hyperactivity and hyperexcitability in neuropathic rats [J]. Neurosci Lett, 2000,283: 153-156.
93. Wilson JA, Garry EM, Anderson HA, et al. NMD A receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists [J]. Pain, 2005, 117: 421-432.
94. Iwata H, Takasusuki T, Yarnaguchi S, Hori Y. NMDA receptor 2B subunit-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-injured neuropathic mice [J]. Brain Res, 2007,1135: 92-101.
95. Minoru Narita, Kan Miyoshi, Michiko Narita, et al. Changes in function of NMDA receptor NR2B subunit in spinal cord of rats with neuropathy following chronic ethanol consumption [J]. Life Sciences, 2007, 80: 852-859.
96. Isaev D, Gerber G, Park SK, et al. Facilitation of NMDA-induced currents and Ca~(2+) transients in the rat substantia gelatinosa neurons after ligation of L5-L6 spinal nerves [J]. NeuroReport, 2000,11: 4055-4061.
97. Xu L, Mabuchi T, Katano T, et al. Nitric oxide (NO) serves as a retrograde messenger to activate neuronal NO synthase in the spinal cord via NMDA receptors [J]. Nitric Oxide, 2007,17:18-24.
98. Tan PH, Yang LC, Shih HC, et al. Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat [J]. Gene Ther, 2005, 12:59-66.
99. katharine Walker, Alyson J, et al. Animal models for pain research [J]. Molecular Medicine Today, 1999, 5: 319-321.
100. Hylden JL, Anton F, Nahin RL. Spinal lamina I projection neurons in rat: collateral innervation of parabrachial area and thalamus [J]. Neuroscience, 1989, 28: 27-37.
101. Bendele A, McComb J, Gould T, et al. Animalmodels of arthritis: relevance to human disease [J]. Toxicol Pathol, 1999,27: 134-142.
102. Hunskaar S, Hole K. The formalin test: dissociation between in flammatory and non-inflammatory pain [J]. Pain, 1987, 30: 103-114.
103. Chen J, Koyama n, Yokota T. Effects of subcutaneous formalin on responses of dorsal horn wide dynamic range neurons and primary afferent neurons in the cat [J]. Pain res, 1996,11:71-83.
104. Clavelou P, Dallel R, Orliaguet T, et al. The orofacial formalin test in rats: effects of different formalin concentrations [J]. Pain, 1995, 62: 295-301.
105. Abbot FV, Franklin BJ, Westbrook RF. The formalin test: scoring properties of the first and second phases of the pain response in rats [J]. Pain, 1995, 60: 91-102.
106. Tjolsen A, Berge OG, Hunskaar S, et al. The formalin test an evaluation of the method [J]. Pain, 1992, 51(1): 5-8.
107. Puig S, Sorkin LS. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity [J]. Pain, 1996, 64: 345-355.
108. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man [J]. Pain, 1988, 33: 87-107.
109. Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury [J]. Pain, 1990,43: 205-218.
110. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat [J]. Pain, 1992, 50: 355-363.
111. Isabelle D, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain [J]. Pain, 2000, 87: 149-158.
112. Joachim S, Andrea A, Claudiu M. Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats [J]. Pain, 2008,138(1): 130-142.
113. Woolf CJ, Chong MS. Preemptive analgesiat reating postoperative pain by preventing the establishment of central sensitization [J]. Anesth Analg, 1993, 77: 362-379.
114. Katz J , Cohen L. Preventive analgesia is associated with reduced pain disability 3 weeks but not 6 months after majorgynecologic surgery by laparotomy [J]. Anest hesiology, 2004,101: 169-174.
115. Kissin I. Preemptive analgesia [J]. Anesthesiology, 2000,93:1138-1143.
116. Dahl JB, Moiniche S. Preemptive analgesia [J]. Br Med Bull, 2004, 71(1): 13-27.
117. RandallL O, Selitto JJ. A method for measurement of analgesic activity on inflammed tissue [J]. Arch Lit Pharmacodyn, 1957, 61: 409-419.
118. Suzuk iR, Chapman V. The effectiviness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain [J]. Pain, 1999, 80: 215-281.
119. Kawakami M, Tamaki J, Hashizume H, et al. The role of phosphor-lipaseA2 and nitric oxide in pain related behavior prodcued by an allograft of intervertebral disc materical to the sciatic nerve of the rat [J]. Spine, 1997,20(10): 1074-10791.
120. Carlton SM, Lekan HA, Kim SH, et al. Behavioral manifestations of an experimental model for peripheral neuropathy produced by spinal nerve ligation in the primate [J]. Pain, 1995, 56: 2155-21661.
121. Hargreaves K, Dubner R, Brown F, et al. Anew and sensitive method for measuring thermal nociception in cutaneous hyperalgesia [J]. Pain, 1988, 32: 77-88.
122. Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoidspace [J]. Physiol Behav 1976,17:1036-7.
123.Kyung ML,Sang MJ,Eun SP,Activation of transcription factor c-jun in dorsal root ganglia induces VIP and NPY upregulation and contributes to the pathogenesis of neuropathic pain[J].Experimental Neurology,2007,204:467-472.
124.Hu P,McLachlan EM.Distinct functional types of macrophage in dorsal root ganglia and spinal nerves proximal to sciatic and spinal nerve transections in the rat [J].Exp Neurol 2003,184:590-605.
125.Schafers M,Lee DH,Brors D,Yaksh TL,Sorkin LS.Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation[J].J Neurosci,2003,23:3028-3038.
126.Tsuda M,Inoue K,Salter MW.Neuropathic pain and spinal microglia:a big problem from molecules in "small" glia[J].Trends Neurosci,2005,28:101-107.
127.Prast H,Philippu A.Nitric oxide as modulator of neuronal function[J].Prog Neurobiol,2001,64:51-68.
128.Omote K,Hazama K,Kawamata T,et al.Peripheral nitric oxide in carrageenan-induced inflammation[J].Brain Res,2001,912:171-175.
129.赵忠球.一氧化氮与脊髓水平的痛觉传递和调制[J].解剖科学进展,2002,8:240-244.
130.Elfering SL,Sarkela TM,Giulivi C.Biochemistry of mitochondrial nitric-oxide synthase[J].J Biol Chem,2002,277:38079-38086.
131.Lacza Z,Pankotai E,Csordas A,et al.Mitochondrial NO and reactive nitrogen species production:does mtNOS exist[J]? Nitric Oxide,2006,14:162-168.
132.Tao F,Tao YX,Mao P,et al.Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase[J].Neurosci,2003,120:847-854.
133.Mungrue IN,Bredt DS,Stewart DJ,Husain M.From molecules to mammals:what's NOS got to do with it[J]? Acta Physiol Scand,2003,179:123-135
134.Hope BT,Michael GL,Knigge KM,Vincent SR.Neuronal NADPH-diaphorase is a nitric oxide synthase[J].Proc Natl AcadSci USA,1991,88:2811-2814.
135.Wiesenfeld-Hallin Z,Hao JX,Xu XJ,Hokfelt T.Nitric oxide mediates ongoing discharges in dorsal root ganglion cells after peripheral nerve injury[J]. Neurophysiol,1993,70:2350-2353.
136.Guhring H,Gorig M,Ates M,Ovidiu C,Zeilhofer HU,Pahl A,et al.Suppressed injury-induced rise in spinal prostaglandin E2 production and reduced early thermal hyperalgesia in iNOS-decient mice[J].Neurosci,2000,20:6714-6720.
137.Garry MG,Walton LP,Davis MA.Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from the spinal cord is mediated by nitric oxide but not by cyclic GMP[J].Brain Res,2000,861:208-219.
138.Fujita T,Kamisaki Y,Yonehara N.Nitric oxide-induced increase of excitatory amino acid levels in the trigeminal nucleus caudalis of the rat with tactile hypersensitivity evoked by the loose-ligation of the inferior alveolar nerves[J].Neurochem,2004,91:558-567.
139.郭新华,杨永忠等.角叉菜胶炎性痛诱导的大鼠脊髓后角一氧化氮合酶的变化角叉菜胶炎性痛诱导的大鼠脊髓后角一氧化氮合酶的变化[J].邯郸医学高等专科学校学报,2005,18(2):89-91.
140.Miyasaka N,Hirata Y.Nitric oxide and inflammatory arthritides[J].LifeSci.1997,61:2073-2081.
141.Yueh-Ling Hsieh.Effects of Ultrasound and Diclofenac Phonophoresis on Inflammatory Pain Relief:Suppression of Inducible Nitric Oxide Synthase in Arthritic Rats[J].Physical Therapy.2006,86(1):39-50.
142.Almberg AB,Yaksh TL.Spinal nitric oxide synthesis inhibition blocks NMDA induced thermal hyperalgesia and produces antionciception in the formalin test in rats[J].Pain,1993,54:291.
143.Yamamoto T,Shimoyarna N,Mizuguchi T.Notric oxide synthaseinhibitor blocks spinal sensitization induced by formalin injection into the rat paw[J].Anesth Analg,1993,77:886-889.
144.Meller ST,Cummings CP,Traub RJ,et al.The role of nitricoxide in the development and maintenance of the hyperalgesia produced by intraplantar injection of carrageenan in the rat[J].Neuroscience,1994,60:367-369.
145.Takano Y,Kuno Y,Sato E,et al.Hyperalgesia induced by in-trathecal administration of nitroglycerin involves NMDA receptor activation in the spinal cord[J].Masui, 1997,46:1354-1358.
146. Michael KB, Nurcan U, et al. Differences in inflammatory pain in nNOS-, iNOS- and eNOS- deficient mice [J]. Eur J. Pain, 2007, 11(7): 810-818.
147. Chu YC, Yun GA, Skinner J. Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain [J]. Pain, 2005, 119, 113-123.
148. Hong YG, Chen TG, Hu ZJ. Modulation of NMDA receptors by intrathecal administration of the sensory neuron-specific receptor agonist BAM8-22 [J]. Neuropharmacology, 2008, 54(5): 796-803.
149. Martinez Garcia F, Novejarque A, Landete JM , et al. Distribution of calcitonin gene related peptide like immunoreactivity in the brain of the lizard podarcis hispanica [J]. J Comp Neurol, 2002, 447(2): 99-113.
150. Lanuza E, Davies DC, Landete JM, et al. Distribution of CGRP like immunoreactivity in the chick and quail brain [J]. J Comp Neurol, 2000, 421 (4): 515-532.
151. Ma W, Chabot JG, Powell KJ, et al. Localization and modulation of calcitonin gene related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems [J]. Neuroscience, 2003,120(3): 677-694.
152. Landry M, Aman K, Dostrovsky J, et al. Galanin expression in adult human dorsal root ganglion neurons: initial observations [J]. Neuro-science, 2003, 117(4): 795-809.
153. Ohtori S, Takahashi K, Chiba T, et al. Phenotypic inflammation switch in rats shown by calcitonin gene-related peptide immunoreactive dorsal root ganglion neurons innervating the lumbar facet joints [J]. Spine, 2001,26(9):1009-1013.
154. Calza L, Pozza M, Zanni M, et al. Peptide plasticity in primary sensory neurons and spinal cord during adjuvant-induced arthritis in the rat: An imrnunocytochemical and in situ hybridization study [J]. Neuroscience, 1998, 82 (2): 575-589.
155. Richard L. Margaret R. Adjuvant-induced inflammation of rat paw is associated with altered calcitonin gene-related peptide immunoreactivity within cell bodies andperipheral endings of primary afferent neurons [J]. Journal of comparative neurology,1994,349:475-485.
156.Staton P,Bountra I,Chessell,ND.Changes in dorsal root ganglion CGRP expression in a chronic inflammatory model of the rat knee joint:Differential modulation by rofecoxib and paracetamol[J].European Journal of Pain,2007,11(3):283-289.
157.Zhang RX,Mi ZP,Qiao JT.Changes of spinal substance P,calcitonin gene-related peptide and neurotensin in rats in response to formalin induced pain[J].Regul Pept,1994,14(1):25-32.
158.Limmroth V,Katsarava Z,Lideert B,et al.An in vivo rat model to study calaitonin gene-related peptide release following activation of the trigeminal vascular system [J].Pain,2001,92(122):101-106.
159.Ballet S,Aubel B,Mauborgne A,et al.The novel analgesic,cizolirtine,inhibits the spinal release of substance P and CGRP in rats[J].Neuropharmacology,2001,40(4):578-589.
160.Leem JW,Gwak YS,Lee EH,et al.Effects of iontophoretically applied substance P,calcitonin gene-related peptide on excitability of doral horn neuroes in rats [J].Yonsei Med J,2001,42(1):74-83.
161.Yu LC,Hansson P.Effects of calcitonin gene-related peptide antagonist CGRP8-37on withdrawal responses in rats with inflammation[J].Br J Pharmacol,1998,347(223):275-282.
162.李桐楠,李清君,李文斌等.CGRP受体拮抗剂CGRP8-37对甲醛炎性痛大鼠自发痛反应及脊髓后角NOS表达和NO含量的影响[J].中国应用生理学杂志,2004,20(3):291-295.
163.Ballet S,Aubel B,Mauborgne A,et al.The novel analgesic,cizolirtine,inhibits the spinal release of substance P and CGRP in rats[J].Neuropharmacology,2001,40(4):5782-5891.
164.Sun RQ,Lawand NB,Willis WD.The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin[J].Pain,2003,104(122):2012-2081.
165.Zhang L,Hoff AO,Wimalawansa SJ,et al.Arthritic calcitonin/alpha calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity [J]. Pain, 2001, 89(223): 265-273.
166. Patrizia Aimar, Lucia Pasti, Giorgio Carmignoto, Adalberto Merighi. Nitric Oxide-Producing Islet Cells Modulate the Release of Sensory Neuropeptides in the Rat Substantia Gelatinosa [J]. The Journal of Neuroscience, 1998, 18(24): 10375-10388.
167. Aimi Y, Fujimura M, Vincent SR, et al. Localization of NADPH diaphorase containing neurons in sensory ganglia of the rat [J]. J Com Neurol, 1991, 306(3): 328-392.