摘要
肾上腺髓质素(adrenomedullin,AM)是CGRP家族的一员,在结构和功能上与CGRP有一定的相似性。最近研究表明AM是一种与疼痛有关的神经肽。内源性阿片肽牛肾上腺髓质22肽(Bovine adrenal medulla 22 peptides,BAM22)可通过与μ-、δ-和κ-阿片受体结合参与了伤害性信息的调控。但它们在炎症痛和神经病理性痛的作用尚不清楚。
本实验应用了行为学、免疫组织化学技术。研究了AM在正常大鼠脊髓背角和DRG的表达情况;观察AM特异性受体拮抗剂AM_(22-52)对CFA炎症模型大鼠热痛觉阈值,AM、CGRP和nNOS表达的影响,探讨AM及其受体在炎症过程中的作用;研究神经损伤后DRG中BAM22的表达,探讨BAM22对神经病理性痛的作用,进一步了解神经病理性痛的发病机制。
结果发现:足底注射CFA会引起脊髓背角浅层和DRG中小型神经元AM-IR的表达增加;鞘内注射AM受体特异性拮抗剂AM_(22-52),翻转了CFA引起的热痛觉阈值降低及脊髓背角和DRG内AM、CGRP、nNOS的表达增加;L5脊神经结扎后,结扎侧L4-6中DRG BAM22-IR,IB4~+细胞和双标细胞都明显降低,L5下降最明显。结果提示:脊髓背角和DRG中的AM参与了伤害性信息的传递,其作用是通过激活AM受体来实现的。BAM22可表达于非肽能类神经元中。神经结扎后,结扎侧DRG神经元BAM22表达下调,提示内源性阿片肽减少,可能是神经病理痛的发病机制之一。
Adrenomedullin (AM) is a member of the Calcitonin gene-related peptide (CGRP) family and shares similarities in structure and function with CGRP. Recently it was indicated as a pain related peptide. Bovine adrenal medulla 22 (BAM22), one of the cleavage products of proenkephalin A, binds toμ-,δ-andκ- opioid receptors with similar affinities . BAM22 exerts important modulatory actions on nociception at the spinal level. The present study was designed to investigate the role of AM or BAM22 in inflammatory and neuropathis pains
Following intraplantar injection of CFA into one hindpaw, the expression of AM-IR in the superficial laminar of the spinal cord and small-size DRG neurons on ipsilateral side was increased. Moreover, CFA-induced hyperalgesia in inflamed paw was reversed by intrathecal administration of AM_(22-52) (10 nmol). Furthermore, AM_(22-52) also reduced the expression of AM, CGRP and nNOS in the spinal dorsal horn and DRG. Spinal Nerve ligation reduced BAM22 in DRG.
The results suggest that the increase of AM in the spinal cord and DRG contributed to inflammatory pain, downregulation of the endogenous opioid peptides may be ascribed for the induction of neuropathic pain.
引文
1. Hylden JL, Anton F, Nahin RL. Spinal lamina I projection neurons in rat: collateral innervation of parabrachial area and thalamus. Neuroscience, 1989, 28:27-37.
2. Chen J, Koyama N.Differential activation of spinal dorsal horn units by subcutaneous formalin in jection in the cat:an electrophysiological study.Exp Brain Res, 1998,118(1): 14.
3. 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. Pain res,1996,11:71-83.
4. Puig S, Sorkin LS. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 ac tivity. Pain 1996,64:345-355.
5. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain, 1988,32:77-88.
6. Merskey H. Clarifying definition of neuropathic pain. Pain, 2002, 96:408-409.
7. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensationlike those seen in man. Pain, 1988, 33:87-107.
8. Seltzer Z, Dubner R, Shir Y.A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury.Pain, 1990,43(2):205-18.
9. Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain, 2000, 87 :149-158.
10. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain, 1992, 50:3552363.
11. James N,Camp bell, Richard A. Mechanisms of Neuropathic Pain.Neuron, 2006,52(1):77-92
12. Kitamura K, Kangawa K, Kawamoto M, et al .Adrenomedullin: a novel hypotensive pep tide isolated from human pheochromocytoma. Biochem Biophys Res Commun,1993, 192(2): 553-560.
13. Poyner DR, Sexton PM, Marshall I, et al. International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev. 2002; 54:233-46.
14. Sugo S, Minamino N, kangawa K, et al. Endothelial cells actively synthesize and secret adrenomedullin. Biopsy's Rees Common, 1994, 201: 1160
15. Kitamura K, Kato J , Kawamoto M , et al. The Intermediate Form of Glycine-Extended Adrenomedullin is the Major Circulating Molecular Form in Human Plasma. Biochem Biophys Res Commun, 1998, 244 (2) :551-555.
16. Sugo S, Minamino N, Shiji H, et al. Interteukin-1, tumor necrosis factor an d lipopolysaccharide additively stimulate production of adrenomed ullin in v- ular smooth muscle cells. Biochem Biophys Res Commun. 1995; 207(1): 25.
17. Hay DL , Smith DM. Adrenomedullin receptors: molecular identity and function .Peptides, 2001, (11) :1753-1763.
18. Aldecoa A, Gujer R, Fischer JA, et al. Mammalian calcitonin receptor-like receptor/receptor activity modifying protein complexes define calcitonin gene-related peptide and adrenomedullin receptors in Drosophila Schneider2cells.FEBS Lett, 2000, 471 (2-3) :156-160.
19. Born W, Muff R, Fischer JA. Functional interaction of G protein-coupled receptors of the adrenomedullin peptide family with accessory receptor-activity-modifying proteins (RAMP). Microsc Res Tech, 2002, 57 (1) : 14-22.
20. Frash NJ, Wise A, Brown J. et al. The amino terminus of receptor activity modifying proteins is a critical determinant of glycosylation state and ligand binding of calcitonin receptor-like receptor. MolParmacal, 1999, 55: 1054-1059
21. Zumpe ET, Tilakaratne N, Fraser NJ, et al. Multiple ramp domain are required for generation of amylin receptor phenotype from the calcitonin receptor gene product Biochem Biophys Res Commun, 2000, 267: 368-372
22. Wang P. Andrenomedulin and cardiovascular responses in sepsis. Peptides, 2001, 22(11): 1835-1840.
23. Evans BN, Resenblatt MI, Mnayer LO. CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedulin receptors. J BiolChem, 2000, 275(40): 31438-31443.
24. Prado MA, Evans-Bain B, Oliver KR, et al. role of the CGRP receptor component protein (RCP) in adrenomedulin receptor signal transduction. Peptides, 2001, 22(11): 1773-1781
25. Juaneda C, Dumont Y, Quirion R. The molecular pharmacology of CGRP and related peptide receptor subtypes. Trends Pharmacol Sci, 2000, 22 (11) :432-438
26. Kamoi, H., et al. "Adrenomedullin inhibits the secretion of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, from rat alveolar macrophages." Biochem.Biophys.Res.Commun. 211.3 (1995): 1031-35.
27. Isumi, Y, et al. "Adrenomedullin stimulates interleukin-6 production in Swiss 3T3 cells." Biochem.Biophys.Res.Commun. 244.2 (1998): 325-331.
28. Isumi, Y, et al. "Adrenomedullin suppresses interleukin-1 beta-induced tumor necrosis factor-alpha production in Swiss 3T3 cells." FEBS Lett. 463.1-2 (1999): 110-114.
29. Nishitani, Y, et al. "Imbalance between interleukin-6 and adrenomedullin mRNA levels in peripheral blood mononuclear cells of patients with lupus nephritis." Clin.Exp.Immunol. 124.2 (2001): 330-336.
30. Chu, D. Q., et al. "The calcitonin gene-related peptide (CGRP) antagonist CGRP(8-37) blocks vasodilatation in inflamed rat skin: involvement of adrenomedullin in addition to CGRP." Neurosci.Lett. 310.2-3 (2001): 169-72.
31. Hippenstiel, S., et al. "Adrenomedullin reduces endothelial hyperpermeability." CircRes. 91.7 (2002): 618-25.
32. Clementi, G., et al. "Antiinflammatory activity of adrenomedullin in the acetic acid peritonitis in rats." Life Sci. 65.15 (1999): L203-L208.
33. Chu, D. Q., et al. "A comparative study of the ability of calcitonin gene-related peptide and adrenomedullin(13 - 52) to modulate microvascular but not thermal hyperalgesia responses." Br.J.Pharmacol. 130.7(2000): 1589-1596.
34. Kim, W., et al. "Adrenomedullin reduces VEGF-induced endothelial adhesion - molecules and adhesiveness through a phosphatidylinositol 3'-kinase pathway." Arterioscler.Thromb.Vasc.Biol. 23.8 (2003): 1377-1383.
35. Ando, K. and T. Fujita. "Lessons from the adrenomedullin knockout mouse." Regul.Pept. 112.1-3 (2003): 185-188.
36. Agata, J., et al. "Adrenomedullin gene delivery inhibits neointima formation in rat artery after balloon angioplasty." Regul.Pept. 112.1-3 (2003): 115-120.
37. Shichiri, M., et al. "Adrenomedullin is an autocrine/paracrine growth factor for rat vascular smooth muscle cells." Regul.Pept. 112.1-3 (2003): 167-73.
38. Shimosawa T , Matsui H , xing G, et al . Organ-protective effects of adrenomedullin[J]. Hypertens Res, 2003, 26(Suppl): S109 - S112.
39. Shiondo T, Kurihara H, Maemura K, et al. Hypotemion and resistance to lipopolysaccharide- induced shock in transgenic mice over expressing adrenomedullin in their vasculature. Circulation, 2000, 101(19): 2309-2316.
40. Westphal M, Stubbe H, Bone HG, et al. Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep. Biochem Biophys Res Commun, 2002, 296(1): 134-138
41. Ma, W., J. G. Chabot, and R. Quirion. "A role for adrenomedullin as a pain-related peptide in the rat." Proc.Natl.Acad.Sci.U.S.A 103.43.2006,16027-16032.
42. Zhuang, Z. Y., et al. "Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPVl sensitization." J.Neurosci. 2004 ,24 (38): 8300-8309.
43. Guo, A., et al. "Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites." Eur.J.Neurosci. 1999,11 (3): 946-958.
44. Ma, W., et al. "Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems." Neuroscience, 2003 ,120 (3): 677-694.
45. Ohtori S , Takahashi K, Chlba T , et al. Substance P and calcitonin gene-related peptide immunoreactive sensory DRG neurons innervating the lumbar facet joints in rats.AutonNeurosci,2000,86(122):13-17
46. 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.Spine ,2001,26(9): 1009-1013
47.Zhang RX,Mi ZP,Qiao J T.Changes of spinal substance P,calcitonin gene-related peptide and neurotensin in rats in response to formalin induced pain.Regul Pept,1994,14(1):25-32
48.刘锐明,景玉宏,王德贵.不同程度的疼痛刺激对大鼠脊髓CGRP表达的影响.中国医学理论与实践,2004,1:38-39
49.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.Pain,2001,92(122):101-106
50.Ballet S,Aubel B,Mauborgne A,et al.The novel analgesic,cizolirtine,inhibits the spinal release of substance P and CGRP in rats.Neuropharmacology,2001,40(4):578-589.
51.Nohr D,Schafer MK,Persson S,et al.Calcitonin gene-related peptide gene expression in collagen induced arthritis is differentially regulated in primary afferents and motoneurons:influence of glucocorticoids.Neuroscience,1999,9(2):759-773.
52.宋雪松,高金贵,孙木,杨桐伟,王凡.背根神经节压迫对大鼠痛行为及脊髓背角内降钙素基因相关肽的影响.中华麻醉学杂志,2004,24(1):44-47.
53.Salmon AM,Damaj MI,Marubio LM,et al.Altered neuro adaptation in opiate ependence and neurogenic inflammatory nociception in alpha CGRP-deficient mice.Nat Neurosci,2001,4(4):357-358.
54.Sebastien Ballet,Bertrand Aubel,Annie Mauborgne.The novel analgesic,cizolirtine,inhibits the spinal release of substance P and CGRP in rats.Neuropharmacology,2001,40:578-589.
55.Yu L C,Hansson P.Effects of calcitonin gene-related peptide antagonist CGRP8-37on withdrawal responses in rats with inflammation.Br J Pharmacol,1998,347(223):275-282.
56.Lofgren O,Yu Lc,Theodorsson E,et al.Intrathecal CGRP(8237) results in a bilateral increase in hindpaw withdrawal latency in rats with a unilateral thermal injury.Neuropeptides,1997,31(6):601-607.
57.Yu L C,Hansson P,Lundeberg T.The calcitonin gene-related peptide antagonist CGRPS-37 increases the latency to withdrawal responses bilaterally in rats with unilateral experimental mononeuropathy, an effect reversed by naloxone. Neuroscience, 1996, 71(2):523-531.
58. 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 .Yonsei Med J,2001,42(1):74-83.
59. Zhang L , Hoff AO ,Wimalawansa SJ ,et al. Arthritic calcitonin/alpha calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity. Pain ,2001 ,89 (223) :265-273
60. Satoh M. Transmission and modulation of nociceptive information in the spinal dorsal horn .Nippon Yakurigaku Zasshi, 1993,101(5): 289-298.
61. Pecile A, Guidobono F, Netti C.Calcitonin gene-related peptide: antinociceptive-activity in rats, comparison with calcitonin. Regul Pept, 1987, 18(34):189
62. Li N,LundebergT,Yu LC. Involvement of CGRPand CGRP1 receptor in nociception in the nucleus accumbens of rats, Brain Res, 2001, 901: 161-166.
63. Bloch, B. et al., Detection of the messenger RNA coding for preproenkephalin A in bovine adrenal by in situ hybridization. Regul.Pept.1984, 8.4: 345-54.
64. Maderdrut, J.L., Merchenthaler, I., Sundberg, D.K., Okado, N. & Oppenheim, R.W.Distribution and development of proenkephalin-like immunoreactivity in the lumbar spinal cord of the chicken. Brain Res.1986, 377: 29-40.
65. Khachaturian, H., Lewis,M.E.& Watson,S.J. Colocalization of proenkephalin peptides in rat brain neurons/Brain Res.1983,279: 369-373.
66. Khachaturian, H., M. E. Lewis, and S. J. Watson., Enkephalin systems in diencephalon and brainstem of the rat. J.Comp Neurol, 1983,220.3: 310-20.
67. Garzon, J., Sanchez-Blazquez, P., Hollt, V., Lee, N.M. & Loh, H.H. Endogenous opioid peptides: comparative evalu ation of their receptor affinities in the mouse brain. Life Sci.l983,33:(Suppl 1) 291-294.
68. Lembo P M, Grazzini E, Groblewski T, Donnell D O, Roy M O, Zhang J et al,. Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs.Nat.Neμrosci,2002,5:201-209.
69.Quirion,R.& Weiss,A.S.Peptide E and other proenkephalin-derived peptides are potent kappa opiate receptor agonists.Peptides.1983,4:445-449.
70.Boersma,C.J.,Pool,C.W.,Van Heerikhuize,J.J.& Van Leeuwen,F.W.Characterization of opioid binding sites in the neural and intermediate lobe of the rat pituitary gland by quantitative receptor autoradiography.J.Neuroendocrinol.1994,6:47-56.
71.Sanchez-Blazquez,P.& Garzon,J.Opioid activity of pro-enkephalin-derived peptides in mouse vas deferens and guinea pig ileum.Neurosci.Lett.1985,61:267-271.
72.Dray,A.,Nunan,L.& Wire,W.Proenkephalin A fragments exhibit spinal and supraspinal opioid activity in vivo.J.Pharmacol.Exp.Ther.1985,235:670-676.
73.Davis,T.P.,Hoyer,G.L.,Davis,R & Burks,T.F.Proenkephalin A-derived peptide E and its fragments alter opioid contractility in the small intestine.Eur.J.Pharmacol.1990,191:253-261.
74.方秀斌.神经肽与神经营养因子.北京:人民卫生出版社.2002,23-41.
75.金文桥.内阿片肽.见:邹冈,主编.基础神经药理学.第2版.北京:科学出版社.1999,288-322
76.王营,欧可群.内源性阿片肽的研究进展.四川解剖学杂志.2000,8:227-230.
77.Y.Hong,P.Dai,J.Jiang,X.Zeng.Dual effects of intrathecal BAM22 on nociceptive responses in acute and persistent pain-potential function of a novel receptor,Br.J.Pharmacol.2004,141:423-430.
78.Jadarola,M.J.,Panμla,P.,Majane,E.A.& Yang,Y.T.The opioid octapeptide Met5-enkephalin-Arg6-Gly7-Leu8:characterization and distribution in rat spinal cord.Brain Res.1985,330:127-134.
79.Swain,M.G.,Macarthur,L.,Vergalla,J.& Jones,E.A.Adrenal secretion of BAM-22P,a potent opioid peptide,is enhanced in rats with acute cholestasis.Am.J.Physiol.1994,266:G201-G205.
80.Shanker,G.,and R.K.Sharma.β-Endorphin stimulates corticosterone synthesis in isolated rat adrenal cellsJ.Clin.Endorcrinol.Metab.1982, 54: 656-660.
81. Hollt, V., Haarmann, I., Grimm, C., Herz, A., Tulunay, F.C. & Loh, H.H.Pro-enkephalin intermediates in bovine brain and adrenal medulla: characterization of immunoreactive peptides related to BAM-22P and peptide F. Life Sci.1982, 31: 1883-1886.
82. V. Hollt, F.C.Tulunay, S.K.Woo, H.H.Loh, and A.Herz. Opioid peptides derived from pro-enkephalin A but not that from pro-enkephalin B are substantial analgesics after administration into brain of mice. Eur. J. Pharmacol. 1982,85: 355-356.
83. F.G. Fang, H.L.Fields, and N.M.Lee.Action at the mu receptor is sufficient to explain the supraspinal analgesic effect of opiates. J. Pharmacol. Exp. Ther. 1986, 238: 1039-1044.
84. Xueai Zeng, Hao Huang, Yanguo Hong. Effects of intrathecal BAM22 on noxious stimulus-evoked c-fos expression in the rat spinal dorsal horn. Brain Res.2004,1028: 170-179.
85. Jiang J, Huang J, and Hong Y .Bovine adrenal medulla 22 reverses antinociceptive morphine tolerance in the rat. Behav Brain Res.2006, 569: 38-45.
86. Buckingham, J.C. and T.A.Cooper.Differences inhypothalamo-pituitary-adrenocortical activity in the rat after acute and prolonged treatment with morphine.Neuroendocrinology.1984,38.5: 411-17.
87. Swain,M.G.,J.Vergalla,N.V.Bsrgasa,and E.A.Jones.Acute cholestasis in rats is associated with opioid-mediated suppression of stress-induced ACTH release.Hepatology.1991,14: A428
88. Ipp, E. et al.,Effects of an enkephalin analog on pancreatic endocrine function and glucose homeostasis in normal and diabetic dogs.Endocrinology.1982,111.6: 2110-16.
89. Bunton DC, Petrie MC, Hillier C, et al. The clinical relevance of adrenomedullin: a promising profile? Pharmacol Ther.2004,103:179-201.
90. Harlan, R. E., Shivers, B. D., Romano, G J., Howells, R. D. & Pfaff, D. W.Localization of preproenkephalin mRNA in the rat brain and spinal cord by in situ hybridization. J. Comp Neurol.1987,258: 159-184.
91. Weihe, E. Neurochemical anatomy of the mammalian spinal cord: functional implications. Anat.Anz.1992, 174: 89-118.
92. Sibinga, N.E.S., and A.Goldstein.Opioid peptides and opiid receptors in cells of the immune system.Annμ.Rev.Irnmunol.1988, 6: 219-249.
93. Price T J, Louria M D, Candelario-Soto D, et al. Treatment of trigeminal ganglion neurons in vitro with NGF,GDNF or BDNF: efects on neuronal survival, neurnchemical properties and TRPV1-mediated neuropeptide secretion. BMC Neuroscience, 2005, 6(1):4-18.
94. Ralller M S, Priestley J V, McMahon S B. Functional regeneration ofsensory axons into the adult spinal cord. Nature, 2000, 403(6767): 312-316.
95. Ieelere P, Ekstrom P, Edstrom A, et al. Efects of al celline-derived neurotrophic factor on axonal growth and apoptosis in adult inamnlalian sensory neurons in vitro. Neuroscience, 1998, 82(2): 545-558.
96. owii AA,Gardiner JV, Upton PD, et al. Characterisation and molecular identification : of adrenomedullin binding sites in the rat spinal cord: A comparison with calcitonin gene-related peptide receptors. J Neurochem,1996, 67(5): 2172-2179.
97. Born W, Fischer JA, MuffR. Receptors for calcitonin gene-related peptide, adrenomedullin, and amylin: the contributions of novel receptor-activity-modifying proteins. Receptors Channels .2002,8:201-9.
98. Cottrell GS, Roosterman D, Marvizon JC, et al. Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat. J Comp Neurol .2005,490:239-55.
99. Oliver KR, Kane SA, Salvatore CA, et al. Cloning, characterization and central nervous system distribution Of receptor activity modifying protein in the rat. Eur J Neurosci,2001, 14(5): 618-628.
100.Gibson SJ, Polak JM, Bloom SR, et al. Calcitonin gene-related peptide immunoreactivity in the spinal cord of man and of eight other species. J Neurosci.1984, 4:3101-11.
101.Hokfelt T, Arvidsson U, Ceccatelli S, et al. Calcitonin gene-related peptide in the brain, spinal cord, and some peripheral systems. Ann N Y Acad Sci .1992,657:119-34.
102.Mogil JS, Miermeister F, Seifert F, et al. Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene. Proc Natl Acad Sci USA. 2005,102:12938-43.
103.Edvinsson L. Calcitonin gene-related peptide (CGRP) and the pathophysiology of headache: therapeutic implications. CNS Drugs. 2001,15:745-53.
104.Born W, Fischer JA, MuffR. Receptors for calcitonin gene-related peptide, adrenomedullin, and amylin: the contributions of novel receptor-activity-modifying proteins. Receptors Channels.2002, 8:201-9.
105.Cottrell GS, Roosterman D, Marvizon JC, et al. Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat. J Comp Neurol.2005,490:239-55.
106.Nagakura Y, Okada M, Kohara A, et al. Allodynia and hyperalgesia in adjuvant-induced arthritic rats: time course of progression and efficacy of analgesics. J Pharmacol Exp Ther. 2003, 306:490-7.
107.Hamid SA, Baxter GF. Adrenomedullin: regulator of systemic and cardiac homeostasis in acute myocardial infarction. Pharmacol Ther 2005; 105:95-112.
108.Ling QD, Chien CC, Wen YR, et al. The pattern and distribution of calcitonin gene-related peptide (CGRP) terminals in the rat dorsal following neonatal peripheral inflammation. Neuroreport.2003,14:1919-21.
109.Smith GD, Harmar AJ, McQueen DS, Seckl JR. Increase in substance P and CGRP, but not somatostatin content of innervating dorsal root ganglia in adjuvant monoarthritis in the rat. Neurosci Lett. 1992 Mar 30; 137(2):257-260.
110.Meller S T, Gebhart G F.Nitric oxide (NO) and nociceptive processing in the spinal cord.Pain,1993, 52:127-136
111.Bredt DS,Glatt CE, Hwang PM, Fotuhi M, Dawson TM, Snyder SH. Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron, 1991, 7: 615-624
112.Mungrue I N, Bredt D S, Stewart D J, Husain M. From molecules to mammals: what's NOS got to do with it? Acta Physiol Scand, 2003,179:123-135
113.Wiencken AE, Casagrande VA. Endothelial nitric oxide synthetase (eNOS) in astrocytes: another source of nitric oxide in neocortexGlia, 1999, 26:280-290
114.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, 70:2350-3.
115.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-de.cient mice. J Neurosci, 2000,20: 6714-6720.
116.Garry M G, Walton L P, Davis M A.Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from the spinal cord is mediated by nitric oxide but not by cyclic GMP.Brain Res, 2000, 861: 208 -219.
117.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, 91:558-567 132 E.L.. Heinzen, R.G. Booth, G.M. Pollack, Neuronal
118.Donaldson LF, Harmar AJ, McQueen DS, et al. Increased expression of preprotachykinin, calcitonin gene-related peptide, but not vasoactive intestinal peptide messenger RNA in dorsal root ganglia during the development of adjuvant monoarthritis in the rat. Brain Res Mol Brain Res .1992,16:143-9.
119.Hay DL, Conner AC, Howitt SG, Smith DM, Poyner DR. The pharmacology of adrenomedullin receptors and their relationship to CGRP receptors. J Mol Neurosci.2004, 22:105-113.
120.Hay DL, Howitt SG, Conner AC, Schindler M, Smith DM, Poyner DR. CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors: a comparison of effects of adrenomedullin22-52, CGRP8-37 and BIBN4096BS. Br J Pharmacol .2003,140:477-486.
121.Husmann K, Sexton PM, Fischer JA, Born W. Mouse receptor-activity-modifying proteins 1, -2 and -3: amino acid sequence, expression and function. Mol Cell Endocrinol.2000,162:35-43.
122.Takhshid MA, Poyner DR, Chabot JG, Fournier A, Ma W, Zheng WH, Owji AA, Quirion R. Characterization and effects on cAMP accumulation of adrenomedullin and calcitonin gene-related peptide (CGRP) receptors in dissociated rat spinal cord cell culture. Br J Pharmacol.2006, 148:459-468.
123.Oku R, Satoh M, Fujii N, Otaka A, Yajima H, Takagi H. Calcitonin gene-related peptide promotes mechanical nociception by potentiating release of substance P from the spinal dorsal horn in rats. Brain Res. 1987,403:350-354
124.Kangrga I, Larew JS, Randic M. The effects of substance P and calcitonin gene-related peptide on the efflux of endogenous glutamate and aspartate from the rat spinal dorsal horn in vitro. Neurosci Lett. 1990,108:155-160.
125.Menard DP, van RD, Kar S, St PS, Sutak M, Jhamandas K, Quirion R. A calcitonin gene-related peptide receptor antagonist prevents the development of tolerance to spinal morphine analgesia. J Neurosci. 1996,16:2342-2351.
126.Bennett DL, Michael GJ, Ramachandran N, Munson JB, Averill S, Yan Q, McMahon SB, Priestley JV.A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury. J Neurosci. 1998,18:3059-3072.
127.Bradbury EJ, Burnstock G, McMahon SB.The expression of P2X3 pruinoceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci .1998,12:256-268.
128.Villar MJ, Cortes R, Theodorsson E, Wiesenfeld-Hallin Z, Schalling M,Fahrenkrug J, Emson PC, Hokfelt T.Neuropeptide expression in rat dorsal root ganglion cells and spinal cord after peripheral nerve injury with special reference to galanin. Euroscience.1989, 33:587-604
129.Ossipov MH, Zhang ET, Carvajal C, Gardell L, Quirion R, Dumont Y,Lai J, Porreca F.Selective mediation of nerve injury-induced tactile hypersensitivity by europeptide Y. J Neurosci.2002,22:9858-9867.
130.Waxman SG, Kocsis JD, Black JA. Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons and is reexpressed following axotomy. J Neurophysiol. 1994, 72:466-470.
131.Lai J, Gold MS, Kim CS, Bian D, Ossipov MH, Hunter JC, Porreca F .Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain.2002,9:143-152.
132.Malan TP, Ossipov MH, Gardell LR, Ibrahim M, Bian D, Lai J, Porreca F.Extraterritorial neuropathic pain correlates with multisegmental elevation of spinal dynorphin in nerve-injured rats. Pain.2000,86:185-194.
133.Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain.1992,5:355-363.
134.Vos BP. Strassman AM. Fos expression in the medullary dorsal horn of the rat after chronic constriction injury to the infraorbital nerve. J Comp Neurol, 1995, 357:362-375.
135.Przew locks B, Lason W.Prezw locki R.Neuroscience,1992,46:209-216.
136.Cai, M., Chen,T., Quirion,R., and Hong,Y. The involvement of spinal bovine adrenal medulla 22-like peptide, the proenkephalin derivative, in modulation of nociceptive processing. Eur. J. Neurosci. 2007, 26, 1128-1138.
137.Hokfelt T, Zhang X.and Wiesenfeld-Hallin Z. Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci, 1994,17(8)22-30.
138.Nahin RL, Ren K, De Leon M, et al. Primary sensory neurons exhibit altered gene expression in a rat model of neuropathic pain. Pain, 1994, 58 (1): 95-108.
139.Marchand JE, Wurm WH, Kato T, et al.Altered tachykinin expression by dorsal root ganglion neurons in a rat model of neuropathic pain. Pain, 1994, 58 (2):219-231.
140.Yoon YW, Na HS, Chung JM. Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain, 1996, 64:27-36.
141.Liu X, Eschenfelder S, Blenk KH, et al. Spontaneous activity of axotomized afferent neurons after L5 spinal nerve injury in rats. Pain, 2000, 84:309-318.
142.Michaelis M, Liu X, Janig W. Axotomized and intact muscle afferents but no skin afferents develop ongoing discharges of dorsal root ganglion origin after peripheral nerve lesion. J Neurosci 2000(20):2742-2748.
143.Wu G, Ringkamp M, Hartke TV, et al. Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci, 2001(21):RC140.
144.Jang JH, Kim DW, Sang Nam T, et al. Peripheral glutamate receptors contribute to mechanical hyperalgesia in a neuropathic pain model of the rat. Neuroscience, 2004, 128(1):169-76.
145.Lee SE, Kim JH.Involvement of substance P and calcitonin gene-related peptide in development and maintenance of neuropathic pain from spinal nerve injury model of rat. Neurosci Res. 2007, 58(3):245-9.
146.Wang R, Guo W, Ossipov MH, et al. Glial cell line-derived neurotrophic factor normalizes neurochemical changes in injured dorsal root ganglion neurons and prevents the expression of experimental neuropathic pain. Neuroscience 2003;121 (3):815-24
147.Farinas, I. and Reichardt, L.F. Neurotrophic factors and their receptors: implications of genetic studies. Neurosciences. 1996.8:133-143.
148.Lewin, G R. and Y. A. Barde. "Physiology of the neurotrophins." Annu.Rev.Neurosci. 1996 ,19,: 289-317
149.Snider WD, Silos-Santiago I.Dorsal root ganglion neurons require functional neurotrophin receptors for survival during development. Philos Trans R Soc Lond B Biol Sci,1996.351:395-403
150.Snider, W.D., and Wright, D.E. Neurotrophins cause a new sensation. Neuron , 1996.16, 229-232.
151.Molliver DC, Wright DE, Leitner ML, et al. IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron, 1997, 19(4): 849-861.
152.Hofbauer KH, Schoof E, Kurtz A, Sandner P (2002) Inflammatory cytokines stimulate adrenomedullin expression through nitric oxide-dependent and -independent pathways. Hypertension 39:161-167
153.Kubo AN, Isumi MY, KangawaK, et al. Adrenomedullin production is correlated with differentiation in human leukemia cell line and peripheral blood monocytes . FEBS Lett, 1998, 426(2): 233-237.
154.Kubo AN, Minamino A, Isumi Y, et al. Production of adrenomedullin in macrophage cell line and peritoneal macrophage. J Biol Chem, 1998, 273(27): 16730-16738.