Functional Analysis of Distinct Nociceptor Populations

周围神经性疼痛在美国影响着超过380万人，是最具挑战性的形式之一 慢性疼痛需要管理，主要是因为潜在的生理和分子机制是 人们对此知之甚少。更好地理解疼痛的基本机制将导致 开发新的止痛疗法。刺激诱发的疼痛起始于残留的初级传入纤维 神经损伤后完好无损，但对完整的邻近神经元发生的功能变化知之甚少 受伤后受到自然高温或机械刺激。因此，这项提案的一个总体目标是明确 参与周围神经病的完整皮肤初级传入神经元的功能变化 疼痛。瞬时受体电位香草酸1(TRPV1)受体是一种基本的分子整合因子 皮肤传入神经元的物理和化学刺激、外部刺激和内源性刺激。TRPV1 毫无疑问，它与炎性热痛觉过敏有关，但人们对它的作用知之甚少(S) TRPV1在神经损伤疼痛中的作用。来自我的实验室和其他人的几行初步数据 提示TRPV1与热痛觉过敏和伴随的机械性痛觉异常有关 神经损伤。因此，这一提议将检验TRPV1在神经损伤中发挥作用的总体假设- 通过促进相邻完整初级传入神经元对热的敏化来诱导疼痛行为 以及机械刺激和神经损伤后自发活动的表达。通过使用 皮肤胞体和末端的行为分析和电生理记录技术 感觉神经元，并通过在野生型小鼠上进行平行实验，用一种新型的、高度 选择性的TRPV1拮抗剂，在TRPV1基因缺失的小鼠中，我们将检验以下三个特定假设：1) TRPV1参与神经损伤诱导的热和机械行为过敏；2)TRPV1 参与神经损伤诱导的完整皮肤初级传入神经元的热敏化 3)TRPV1参与神经损伤诱发的自发活动 以及对完整的皮肤传入神经元的机械敏化。了解TRPV1在人类免疫缺陷中的作用 神经损伤诱导的初级感觉神经元疼痛行为敏感化将有助于 新型TRPV1拮抗剂在神经病理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.