Mediators of C-Fiber Response to Partial Nerve Injury

描述（由申请人提供）：周围神经病变是一个主要的临床问题，仅在美国就折磨着大约2000万人。疼痛是一个突出的特征，它通常顽固地抵抗治疗。我们的初步数据表明，大鼠第5腰椎腹侧根横断（L5腹侧根切断术）会导致疼痛行为、c纤维电生理改变和c纤维细胞生物学改变。在神经性疼痛的L5腹侧神经根切断术模型中，c纤维感觉轴突没有直接损伤，但对附近运动轴突的变性反应迅速。退化的和未损伤的轴突在周围神经中混合在一起，但在脊髓、感觉神经节或皮肤中不直接相互作用。我们的中心假设是：周围神经轴突的退化通过扩散因子向未损伤的c -纤维发出信号，从而导致神经性疼痛。目的1是确定未损伤和退化轴突之间的外周神经相互作用在神经性疼痛行为中的作用。这将使用一种新开发的神经性疼痛模型进行研究，该模型将来自近交系供体的退化神经段植入受体动物坐骨神经的开窗上。一种补充的方法是使用L3腹侧神经根切断术来减少周围神经的相互作用；一般来说，L3轴突不进入坐骨神经。目的2是使用相同的模型来检测未损伤的c -纤维对周围神经轴突退化的反应。未损伤c -纤维的反应将通过c -纤维传导速度特性的变化和非髓鞘雪旺细胞有丝分裂的增加来测量。SPECIFIC AIM 3将评估NGF作为神经损伤后释放的潜在扩散因子的作用，该因子负责疼痛行为和神经性c纤维改变。这将通过将上述方法翻译到小鼠物种中来研究，并在通过高亲和力的NGF受体TrkA诱导抑制信号的小鼠品系中研究对这些相同模型的反应。这项研究的长期目标是确定治疗神经性疼痛的治疗靶点。这项研究将在指导职业发展期间进行，强调疼痛研究的先进技能和负责任的科学行为。

DESCRIPTION (provided by applicant): Peripheral neuropathy is a major clinical problem that afflicts about 20 million persons in the U.S. alone. Pain is a prominent feature and it is generally stubbornly resistant to treatment. Our preliminary data have shown that transection of the 5th lumbar ventral root (L5 Ventral Rhizotomy) in rat results in pain behavior, altered C-fiber electrophysiology, and changes in C-fiber cell biology. In the L5 Ventral Rhizotomy model of neuropathic pain, C-fiber sensory axons are not directly injured but respond briskly to degeneration of nearby motor axons. The degenerating and uninjured axons co-mingle in peripheral nerve but do not interact directly in the spinal cord, sensory ganglion or skin. Our central hypothesis is: Degenerating axons in the peripheral nerve signal uninjured C-fibers via diffusible factors and that this leads to neuropathic pain. SPECIFIC AIM 1 is to determine the role of peripheral nerve interactions between uninjured and degenerating axons in neuropathic pain behavior. This will be studied using a newly developed model of neuropathic pain that implants a degenerating nerve segment from an inbred donor over a fenestration in the sciatic nerve of a recipient animal. A complementary approach will be taken by minimizing peripheral nerve interactions using L3 ventral rhizotomy; in general, L3 axons do not enter the sciatic nerve. SPECIFIC AIM 2 is to examine the response of uninjured C-fibers to degenerating axons in peripheral nerve using these same models. The responses of uninjured C-fibers will be measured as changes in C-fiber conduction velocity properties and increased mitosis of nonmyelinating Schwann cells. SPECIFIC AIM 3 will assess the role of NGF, as a potential diffusible factor released after nerve injury that is responsible for pain behavior and neuropathic C-fiber change. This will be studied by translating the above methods into mouse species and studying the responses to these same models in a strain of mice that has inducible inhibition of signaling through the TrkA, high-affinity NGF receptor. The long term objectives of this research are to identify therapeutic targets for the treatment of neuropathic pain. This research will be conducted during a period of mentored career development emphasizing advanced skills in pain research and the responsible conduct of science.