2011 Fiscal Year Final Research Report
GDNF reverses neuropathic pain through mitigation of nerve injury-induced changes in expression of voltage-gated sodium and potassium channels.
| Project/Area Number |
21600016
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
疼痛学
|
|---|
| Research Institution | Hyogo Medical University |
|---|
Principal Investigator |
FUKUOKA Tetsuo 兵庫医科大学, 医学部, 非常勤講師 (90399147)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Kimiko 兵庫医科大学, 医学部, 助教 (70418961)
|
|---|
| Project Period (FY) |
2009 – 2011
|
| Keywords | GDNF / Nav / Kv / DRG / neuropathic pain |
|---|
| 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.
|
