| Project/Area Number |
21600016
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
疼痛学
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| Research Institution | Hyogo Medical University |
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Principal Investigator |
FUKUOKA Tetsuo 兵庫医科大学, 医学部, 非常勤講師 (90399147)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Kimiko 兵庫医科大学, 医学部, 助教 (70418961)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | GDNF / Nav / Kv / DRG / neuropathic pain / A電流 / NPY / BDNF / substance P / 神経因性疼痛モデル |
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| Research Abstract |
Abnormal spontaneous activities of the injured primary afferents have been proposed as one of the pathomechanisms of neuropathic pain following nerve injury. Whereas spinal infusion of glial cell line-derived neurotrophic factor(GDNF) reduces these activities in A-fiber afferents as well as pain behaviors, the molecular mechanism is controversial. The transient A-type potassium current(I_A) controls membrane excitability, and all three members of Kv4 subfamily of voltage-gated potassium channels, Kv4.1-Kv4.3, encode A-type channels. We examined the effect of spinal GDNF infusion on IA as well as expression of Kv4.1-Kv4.3 mRNAs in the injured primary afferent neurons using in situ hybridization histochemistry and in vitro path clamp technique. Axonal injury by L5 spinal nerve ligation(SNL) significantly reduced I_A amplitude of the large neurons in the ipsilateral L5 dorsal root ganglion(DRG) 3 days after surgery. Seven-days long spinal GDNF infusion started at day 3 reversed the IA reduction. In normal L5 DRG, actually all neurons expressed Kv4.1 mRNA, a limited number of TrkA-negative neurons exclusively had Kv4.2, and small neurons that bound Griffonia simplicifolia isolectin B4(IB4+) exclusively expressed Kv4.3.L5 SNL decreased all these mRNAs, and delayed spinal infusion of GDNF reversed the down-regulation of Kv4.1 and Kv4.2, but not Kv4.3.Our data suggest that spinal GDNF treatment should reduce the hyperexcitability of the injured A-fiber afferents by IA recurrence mainly through normalization of Kv4.1 expression. We propose that this is one of the analgesic mechanisms of GDNF on the animal neuropathic pain model.
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