BRAIN and NERVE－神経研究の進歩64巻11号

2012年11月発行

増大特集 痛みの神経学―末梢神経から脳まで

神経障害性疼痛の病態―脊髄後角の分子メカニズム

著者： 山中博樹¹ 野口光一¹

所属機関： ¹兵庫医科大学解剖学講座神経科学部門

ページ範囲：P.1255 - P.1265

文献概要

はじめに

　神経障害性疼痛とは末梢・中枢の神経の損傷に伴って起き得る重篤な難治性の疼痛で，現在までこれに著効する薬剤は少なく，随伴する精神的なうつ症状も含めると神経障害性疼痛は患者の生活の質を低下させるに十分な苦痛を与えている。ヨーロッパでは人口の1/5が慢性痛を経験しており，個人の苦痛に加えて経済的損失は600億ドルに達するといわれている¹⁾。米国での試算では約1億1,600万人が慢性痛に悩まされた経験を持ち，そのうち17.9％は神経障害性疼痛であるとされている²⁾。このように神経障害性疼痛は克服すべき課題であるにもかかわらず，これに対する治療手段には限界がある。昨今明らかになりつつある神経障害性疼痛の発症メカニズムが多岐にわたり，なおかつ発症因子が多様性を示していることが有効な創薬・治療戦略を立てにくい一要因であろう。

　本稿では痛みの重要な中継核である脊髄後角にフォーカスを絞り，現在まで明らかになっている神経障害性疼痛発現の分子メカニズムを概説する。

参考文献

1) Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D: Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 10: 287-333, 2006

2) Toth C, Lander J, Wiebe S: The prevalence and impact of chronic pain with neuropathic pain symptoms in the general population. Pain Med 10: 918-929, 2009

3) Chen Y, Devor M: Ectopic mechanosensitivity in injured sensory axons arises from the site of spontaneous electrogenesis. Eur J Pain 2: 165-178, 1998

4) Liu X, Chung K, Chung JM: Ectopic discharges and adrenergic sensitivity of sensory neurons after spinal nerve injury. Brain Res 849: 244-247, 1999

5) Laird JM, Bennett GJ: An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy. J Neurophysiol 69: 2072-2085, 1993

6) Suzuki R, Dickenson A: Spinal and supraspinal contributions to central sensitization in peripheral neuropathy. Neurosignals 14: 175-181, 2005

7) Kohno T, Moore KA, Baba H, Woolf CJ: Peripheral nerve injury alters excitatory synaptic transmission in lamina II of the rat dorsal horn. J Physiol 548: 131-138, 2003

8) Draganic P, Miletic G, Miletic V: Changes in post-tetanic potentiation of A-fiber dorsal horn field potentials parallel the development and disappearance of neuropathic pain after sciatic nerve ligation in rats. Neurosci Lett 301: 127-130, 2001

9) Xing JL, Hu SJ, Jian Z, Duan JH: Subthreshold membrane potential oscillation mediates the excitatory effect of norepinephrine in chronically compressed dorsal root ganglion neurons in the rat. Pain 105: 177-183, 2003

channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. J Physiol 585: 867-879, 2007

channels in dorsal root ganglion neurons. Am J Physiol Cell Physiol 291: C138-C146, 2006

12) Tulleuda A, Cokic B, Callejo G, Saiani B, Serra J, et al: TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury. Mol Pain 7: 30, 2011

13) Amir R, Michaelis M, Devor M: Membrane potential oscillations in dorsal root ganglion neurons: role in normal electrogenesis and neuropathic pain. J Neurosci 19: 8589-8596, 1999

14) Bauer CS, Nieto-Rostro M, Rahman W, Tran-Van-Minh A, Ferron L, et al: The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J Neurosci 29: 4076-4088, 2009

15) Noguchi K, Kawai Y, Fukuoka T, Senba E, Miki K: Substance P induced by peripheral nerve injury in primary afferent sensory neurons and its effect on dorsal column nucleus neurons. J Neurosci 15: 7633-7643, 1995

16) Miki K, Fukuoka T, Tokunaga A, Noguchi K: Calcitonin gene-related peptide increase in the rat spinal dorsal horn and dorsal column nucleus following peripheral nerve injury: up-regulation in a subpopulation of primary afferent sensory neurons. Neuroscience 82: 1243-1252, 1998

17) Michael GJ, Averill S, Shortland PJ, Yan Q, Priestley JV: Axotomy results in major changes in BDNF expression by dorsal root ganglion cells: BDNF expression in large trkB and trkC cells, in pericellular baskets, and in projections to deep dorsal horn and dorsal column nuclei. Eur J Neurosci 11: 3539-3551, 1999

18) Fukuoka T, Kondo E, Dai Y, Hashimoto N, Noguchi K: Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J Neurosci 21: 4891-4900, 2001

19) Fukuoka T, Tokunaga A, Tachibana T, Dai Y, Yamanaka H, et al: VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation. Pain 99: 111-120, 2002

20) Hudson LJ, Bevan S, Wotherspoon G, Gentry C, Fox A, et al: VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci 13: 2105-2114, 2001

21) Ta LE, Bieber AJ, Carlton SM, Loprinzi CL, Low PA, et al: Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice. Mol Pain 6: 15, 2010

22) Somers DL, Clemente FR: Dorsal horn synaptosomal content of aspartate, glutamate, glycine and GABA are differentially altered following chronic constriction injury to the rat sciatic nerve. Neurosci Lett 323: 171-174, 2002

23) Coderre TJ, Melzack R: Central neural mediators of secondary hyperalgesia following heat injury in rats: neuropeptides and excitatory amino acids. Neurosci Lett 131: 71-74, 1991

24) Kristensen JD, Svensson B, Gordh T Jr: The NMDA-receptor antagonist CPP abolishes neurogenic 'wind-up pain' after intrathecal administration in humans. Pain 51: 249-253, 1992

25) Davar G, Hama A, Deykin A, Vos B, Maciewicz R: MK-801 blocks the development of thermal hyperalgesia in a rat model of experimental painful neuropathy. Brain Res 553: 327-330, 1991

26) Mao J, Price DD, Mayer DJ, Lu J, Hayes RL: Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy. Brain Res 576: 254-262, 1992

27) Seltzer Z, Cohn S, Ginzburg R, Beilin B: Modulation of neuropathic pain behavior in rats by spinal disinhibition and NMDA receptor blockade of injury discharge. Pain 45: 69-75, 1991

28) Leem JW, Choi EJ, Park ES, Paik KS: N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists differentially suppress dorsal horn neuron responses to mechanical stimuli in rats with peripheral nerve injury. Neurosci Lett 211: 37-40, 1996

29) Suzuki R, Matthews EA, Dickenson AH: Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy. Pain 91: 101-109, 2001

30) Gao X, Kim HK, Chung JM, Chung K: Enhancement of NMDA receptor phosphorylation of the spinal dorsal horn and nucleus gracilis neurons in neuropathic rats. Pain 116: 62-72, 2005

31) Abe T, Matsumura S, Katano T, Mabuchi T, Takagi K, et al: Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain. Eur J Neurosci 22: 1445-1454, 2005

32) Mantyh PW, Pinnock RD, Downes CP, Goedert M, Hunt SP: Correlation between inositol phospholipid hydrolysis and substance P receptors in rat CNS. Nature 309: 795-797, 1984

33) Sugiyama H, Ito I, Hirono C: A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature 325: 531-533, 1987

34) Gerber G, Randic M: Participation of excitatory amino acid receptors in the slow excitatory synaptic transmission in the rat spinal dorsal horn in vitro. Neurosci Lett 106: 220-228, 1989

35) Alaluf S, Mulvihill ER, McIlhinney RA: Rapid agonist mediated phosphorylation of the metabotropic glutamate receptor 1 alpha by protein kinase C in permanently transfected BHK cells. FEBS Lett 367: 301-305, 1995

block of NMDA-receptor channels as a mechanism of modulation. Nature 356: 521-523, 1992

37) Miletic V, Bowen KK, Miletic G: Loose ligation of the rat sciatic nerve is accompanied by changes in the subcellular content of protein kinase C beta II and gamma in the spinal dorsal horn. Neurosci Lett 288: 199-202, 2000

38) Fundytus ME, Yashpal K, Chabot JG, Osborne MG, Lefebvre CD, et al: Knockdown of spinal metabotropic glutamate receptor 1 (mGluR(1)) alleviates pain and restores opioid efficacy after nerve injury in rats. Br J Pharmacol 132: 354-367, 2001

39) Yashpal K, Fisher K, Chabot JG, Coderre TJ: Differential effects of NMDA and group I mGluR antagonists on both nociception and spinal cord protein kinase C translocation in the formalin test and a model of neuropathic pain in rats. Pain 94: 17-29, 2001

40) Hua XY, Chen P, Yaksh TL: Inhibition of spinal protein kinase C reduces nerve injury-induced tactile allodynia in neuropathic rats. Neurosci Lett 276: 99-102, 1999

41) Yajima Y, Narita M, Shimamura M, Kubota C, Suzuki T: Differential involvement of spinal protein kinase C and protein kinase A in neuropathic and inflammatory pain in mice. Brain Res 992: 288-293, 2003

42) Fang L, Wu J, Lin Q, Willis WD: Calcium-calmodulin-dependent protein kinase II contributes to spinal cord central sensitization. J Neurosci 22: 4196-4204, 2002

43) Garry EM, Moss A, Delaney A, O'Neill F, Blakemore J, et al: Neuropathic sensitization of behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice. Curr Biol 13: 321-328, 2003

44) Basbaum AI, Fields HL: Endogenous pain control mechanisms: review and hypothesis. Ann Neurol 4: 451-462, 1978

45) Sandkuhler J: The organization and function of endogenous antinociceptive systems. Prog Neurobiol 50: 49-81, 1996

46) Yoshimura M, Nishi S: Primary afferent-evoked glycine- and GABA-mediated IPSPs in substantia gelatinosa neurones in the rat spinal cord in vitro. J Physiol 482 (Pt 1): 29-38, 1995

47) Baba H, Ji RR, Kohno T, Moore KA, Ataka T, et al: Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn. Mol Cell Neurosci 24: 818-830, 2003

48) Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, et al: Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci 22: 6724-6731, 2002

49) Prescott SA, Sejnowski TJ, De Koninck Y: Reduction of anion reversal potential subverts the inhibitory control of firing rate in spinal lamina I neurons: towards a biophysical basis for neuropathic pain. Mol Pain 2: 32, 2006

50) Scholz J, Broom DC, Youn DH, Mills CD, Kohno T, et al: Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J Neurosci 25: 7317-7323, 2005

51) Polgar E, Hughes DI, Arham AZ, Todd AJ: Loss of neurons from laminas I-III of the spinal dorsal horn is not required for development of tactile allodynia in the spared nerve injury model of neuropathic pain. J Neurosci 25: 6658-6666, 2005

52) Polgar E, Todd AJ: Tactile allodynia can occur in the spared nerve injury model in the rat without selective loss of GABA or GABA(A) receptors from synapses in laminae I-II of the ipsilateral spinal dorsal horn. Neuroscience 156: 193-202, 2008

53) Hwang JH, Yaksh TL: The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain 70: 15-22, 1997

54) Malan TP, Mata HP, Porreca F: Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain. Anesthesiology 96: 1161-1167, 2002

55) Eaton MJ, Martinez MA, Karmally S: A single intrathecal injection of GABA permanently reverses neuropathic pain after nerve injury. Brain Res 835: 334-339, 1999

56) Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, et al: BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438: 1017-1021, 2005

57) Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, et al: Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424: 938-942, 2003

58) Beggs S, Salter MW: Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0．Curr Opin Neurobiol 20: 474-480, 2010

59) Gosselin RD, Suter MR, Ji RR, Decosterd I: Glial cells and chronic pain. Neuroscientist 16: 519-531, 2010