Functional Analysis of Distinct Nociceptor Populations

周围神经性疼痛在美国影响超过380万人，并且是最具挑战性的形式之一。 慢性疼痛的管理，主要是因为潜在的生理和分子机制， 不太了解。更好地理解疼痛的基本机制将导致 开发新的疼痛疗法。刺激诱发的疼痛起始于初级传入纤维， 完整的神经损伤后，但很少有人知道发生在完整的，相邻的神经元， 自然热或机械刺激后受伤。因此，本提案的总体目标是， 完整的皮肤初级传入神经元的功能变化，有助于周围神经病变 痛苦瞬时受体电位香草酸1（TRPV 1）受体是一种基本的分子整合剂 物理和化学，外部和内源性刺激的皮肤传入神经元。TRPV1 明确地有助于炎性热痛觉过敏，但对 TRPV 1在神经损伤疼痛中的作用从我的实验室和其他人那里得到的几行初步数据 提示TRPV 1参与伴随的热痛觉过敏和机械性异常性疼痛 神经损伤因此，这项提案将测试TRPV 1在神经损伤中发挥作用的总体假设- 通过促进邻近完整的初级传入神经元对热的敏感性来诱导疼痛行为 和机械刺激以及神经损伤后自发活动的表达。通过使用 行为学分析和电生理记录技术在索马和终端的皮肤 感觉神经元，并在野生型小鼠中进行平行实验， 选择性TRPV 1拮抗剂和TRPV 1缺失小鼠中，我们将测试以下三个具体假设：1） TRPV 1参与神经损伤诱导的热和机械行为超敏反应; 2）TRPV 1 有助于神经损伤诱导的完整皮肤初级传入神经元的热敏感性， TRPV 1参与神经损伤后的自发活动 和完整皮肤传入神经元的机械敏化。了解TRPV 1的作用 神经损伤引起的疼痛行为敏化的初级感觉神经元将有助于 新型TRPV 1拮抗剂在神经性疼痛患者中的开发和应用。

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.