Functional Analysis of Distinct Nociceptor Populations

描述（由申请人提供）：周围神经性疼痛在美国影响超过380万人，是最具挑战性的慢性疼痛形式之一，主要是因为对潜在的生理和分子机制知之甚少。更好地了解疼痛的基本机制将导致新的疼痛治疗方法的发展。刺激诱发的疼痛是在神经损伤后保持完整的初级传入纤维中引发的，但对损伤后自然热或机械刺激在完整的相邻神经元中发生的功能变化知之甚少。因此，本提案的总体目标是确定完整的皮肤初级传入神经元的功能变化，有助于周围神经性疼痛。瞬时受体电位香草酸1（TRPV 1）受体是皮肤传入神经元的物理和化学，外部和内源性刺激的基本分子整合剂。TRPV 1明确地促进炎性热痛觉过敏，但对TRPV 1在神经损伤疼痛中的作用知之甚少。来自我实验室和其他实验室的几条初步数据有力地表明，TRPV 1有助于伴随神经损伤的热痛觉过敏和机械异常性疼痛。因此，本提案将检验以下总体假设：TRPV 1通过促进相邻完整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，在神经损伤诱导的疼痛行为中发挥作用。通过在皮肤感觉神经元的索马体和末梢使用行为测定和电生理记录技术，并通过在用新型的、高选择性TRPV 1拮抗剂处理的野生型小鼠和TRPV 1敲除小鼠中进行平行实验，我们将检验以下三个特定假设：1）TRPV 1参与神经损伤诱导的热和机械行为超敏性; 2）TRPV 1在神经末梢和索马水平参与神经损伤诱导的完整皮肤初级传入神经元的热敏感化; 3）TRPV 1参与神经损伤诱导的完整皮肤初级传入神经元的自发活动和机械敏感化。了解TRPV 1在神经损伤诱导的初级感觉神经元疼痛行为敏化中的作用将有助于开发和使用新型TRPV 1拮抗剂治疗神经病理性疼痛患者。

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.