Mediators of C-Fiber Response to Partial Nerve Injury

描述(申请人提供)：周围神经病是一个主要的临床问题，仅在美国就有大约2000万人受到影响。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，切断大鼠腰5腹根(L5腹根)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。在神经病理性疼痛的L5腹根切断模型中，C纤维感觉神经轴突不是直接损伤的，而是对附近运动神经轴突的变性有快速反应。变性轴突和未损伤轴突在周围神经中混合，但不直接在脊髓、感觉神经节或皮肤中相互作用。我们的中心假设是：周围神经中的轴突退化，通过扩散因子传递未损伤的C纤维信号，从而导致神经病理性疼痛。目的1明确未损伤轴突和变性轴突之间的外周神经相互作用在神经病理性疼痛行为中的作用。这将使用一种新开发的神经病理性疼痛模型进行研究，该模型将近亲交配供体的退化神经节植入受体动物坐骨神经的窗口。通过L3前根切断术减少周围神经的相互作用，将采取补充的方法；一般来说，L3轴突不进入坐骨神经。特异目的2是利用相同的模型检测未损伤的C纤维对周围神经变性轴突的反应。未损伤的C纤维的反应将通过C纤维传导速度特性的改变和无髓鞘雪旺细胞有丝分裂的增加来测量。特定的AIM 3将评估神经生长因子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病理性C纤维的改变。这将通过将上述方法转化为小鼠物种，并在一种通过TrkA高亲和力NGF受体诱导信号抑制的小鼠身上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病理性疼痛的靶点。这项研究将在有指导的职业发展阶段进行，强调疼痛研究的高级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.