Functional Analysis of Distinct Nociceptor Populations

描述(申请人提供)：外周神经性疼痛在美国影响着380万人，是最具挑战性的慢性疼痛形式之一，主要是因为基本的生理和分子机制尚不清楚。更好地了解疼痛的基本机制将导致新的疼痛疗法的发展。刺激诱发的疼痛起始于神经损伤后保持完好的初级传入纤维，但对损伤后完整的相邻神经元在自然热或机械刺激下发生的功能变化知之甚少。因此，这项建议的总体目标是确定导致周围神经病理性疼痛的完整皮肤初级传入神经元的功能变化。瞬时受体电位香草酸1(TRPV1)受体是皮肤传入神经元物理、化学、外部和内源性刺激的基本分子整合因子。TRPV1在炎症性热痛觉过敏中的作用是明确的，但关于TRPV1在神经损伤疼痛中的作用(S)却知之甚少。来自我的实验室和其他实验室的几行初步数据有力地表明，TRPV1与伴随神经损伤的热痛觉过敏和机械性痛觉异常有关。因此，这项提议将检验TRPV1在神经损伤诱导的疼痛行为中发挥作用的总体假设，即TRPV1通过促进邻近完整的初级传入神经元对热和机械刺激的敏化以及神经损伤后自发活动的表达来发挥作用。通过在皮肤感觉神经元胞体和终末使用行为分析和电生理记录技术，并通过在野生型小鼠和TRPV1基因缺失小鼠中进行平行实验，我们将验证以下三个特定假设：1)TRPV1有助于神经损伤诱导的热和机械行为超敏；2)TRPV1有助于神经损伤诱导的初级皮肤传入神经元的热敏化；3)TRPV1有助于神经损伤诱导的自发活动和完整皮肤传入神经元的机械敏化。了解TRPV1在神经损伤诱导的初级感觉神经元痛觉行为敏化中的作用，将有助于开发和使用新型TRPV1拮抗剂治疗神经病理性疼痛。

DESCRIPTION (provided by applicant): Peripheral neuropathic pain affects over 3.8 million in the US and is one of the most challenging forms of chronic pain to manage, primarily because the underlying physiological and molecular mechanisms are poorly understood. A better understanding of basic mechanisms underlying pain will lead to the development of novel pain therapies. Stimulus-evoked pain is initiated in primary afferent fibers that remain intact after nerve injury, but little is known about functional changes that occur in intact, adjacent neurons to natural heat or mechanical stimuli after injury. Therefore, an overall goal of this proposal is to define functional changes in intact cutaneous primary afferent neurons that contribute to peripheral neuropathic pain. The Transient Receptor Potential Vanilloid 1 (TRPV1) receptor is a fundamental molecular integrator of physical and chemical, external and endogenous stimuli for cutaneous afferent neurons. TRPV1 unequivocally contributes to inflammatory heat hyperalgesia, but far less is known about the role(s) of TRPV1 in nerve injury pain. Several lines of preliminary data from my laboratory and others strongly suggest that TRPV1 contributes to both the heat hyperalgesia and mechanical allodynia that accompanies nerve injury. Therefore, this proposal will test the overall hypothesis that TRPV1 plays a role in nerve injury- induced pain behavior by contributing to the sensitization of adjacent intact primary afferent neurons to heat and mechanical stimuli and the expression of spontaneous activity following nerve injury. By using behavioral assays and electrophysiological recording techniques at the soma and terminal of the cutaneous sensory neuron, and by conducting parallel experiments in wild type mice treated with a novel, highly selective TRPV1 antagonist and in TRPV1 null mice, we will test the following three specific hypotheses: 1) TRPV1 contributes to nerve injury-induced heat and mechanical behavioral hypersensitivity; 2) TRPV1 contributes to nerve injury-induced heat sensitization of intact cutaneous primary afferent neurons at the level of the nerve terminal and the soma; 3) TRPV1 contributes to nerve injury-induced spontaneous activity and mechanical sensitization of intact cutaneous afferent neurons. Understanding the role of TRPV1 in nerve injury-induced pain behavior sensitization of primary sensory neurons will contribute to the development and use of novel TRPV1 antagonists in patients with neuropathic pain.