臨床整形外科44巻1号

2009年01月発行

総説

神経因性疼痛とグリア細胞

著者： 井上和秀¹

所属機関： ¹九州大学大学院薬学研究院・薬理学分野

ページ範囲：P.57 - P.64

　神経因性疼痛発症にミクログリアおよびアストロサイトは重要な役割を演じている．各グリア細胞表面の機能分子には，P2X₄，P2X₇，P2Y₁₂受容体などのATP受容体サブタイプ，免疫系受容体，さらにはケモカイン受容体，フラクタルカイン受容体，toll-like receptor 4(TLR-4)，カンナビノイドCB2受容体などがある．これらがどのように役割分担しているのかについてはいまだ不明であり，相互に連関するのか，あるいはそれぞれで機能するのかについては今後の研究により明らかにされなければならない．グリア細胞内シグナリングには各種mitogen-activated protein kinase(MAPK)が関与すると考えられ，それらの機能としては，脳由来神経栄養因子(brain-derived neurotrophic factor：BDNF)や炎症性サイトカインの放出が神経因性疼痛発症に重要と考えられる．

参考文献

1) Abbracchio MP, Burnstock G, Boeynaems JM, et al:International Union of Pharmacology LVIII:update on the P2Y G protein-coupled nucleotide receptors:from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58:281-341, 2006

2) Burnstock G:Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol Rev 58:58-86, 2006

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

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

5) Hynes RO:Integrins:versatility, modulation, and signaling in cell adhesion. Cell 69:11-25, 1992

6) Inoue K, Koizumi S, Tsuda M, et al:Signaling of ATP receptors in glia-neuron interaction and pain. Life Sci 74:189-197, 2003

7) Kobayashi K, Yamanaka H, Fukuoka T, et al:P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J Neurosci 28:2892-2902, 2008

8) Miller G:Neuroscience. The dark side of glia. Science 308:778-781, 2005

9) Nasu-Tada K, Koizumi S, Tsuda M, et al:Possible involvement of increase in spinal fibronectin following peripheral nerve injury in upregulation of microglial P2X(4), a key molecule for mechanical allodynia. Glia 53:769-775, 2006

10) Tanga FY, Raghavendra V, DeLeo JA:Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int 45:397-407, 2004

11) Tanga FY, Nutile-McMenemy N, DeLeo JA:The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci U S A 102:5856-5861, 2005

12) Tanga FY, Raghavendra V, Nutile-McMenemy N, et al:Role of astrocytic S100beta in behavioral hypersensitivity in rodent models of neuropathic pain. Neuroscience 140:1003-1010, 2006

13) Tsuda M, Shigemoto-Mogami Y, Koizumi S, et al:P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778-783, 2003

14) Tsuda M, Inoue K, Salter MW:Neuropathic pain and spinal microglia:a big problem from molecules in "small" glia. Trends Neurosci 28:101-107, 2005

15) Tsuda M, Tozaki-Saitoh H, Masuda T, et al:Lyn tyrosine kinase is required for P2X(4) receptor upregulation and neuropathic pain after peripheral nerve injury. Glia 56:50-58, 2008

16) Tsuda M, Ueno H, Kataoka A, et al:Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling. Glia 56:378-386, 2008

17) Tsuda M, Toyomitsu E, Komatsu T, et al:Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury. Glia 56:579-585, 2008

18) Tozaki-Saitoh H, Tsuda M, Miyata H, et al:P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci 28:4949-4956, 2008

19) Zhuang ZY, Gerner P, Woolf CJ, et al:ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114:149-59, 2005