PRIMARY C NOCICEPTORS AND C SYMPATHETICS IN CRPS

描述（由申请人提供）：周围神经或组织损伤后的慢性神经性疼痛和痛觉过敏/异常性疼痛，无论是否与神经病理学（CRPS II）相关（CRPS I），都是患者的诅咒，逃避治疗和困惑研究人员。外周疼痛感受器（伤害感受器）的功能亢进是神经病（CRPS II）中异常疼痛输入的公认原因，也是CRPS I中脊髓中疼痛信号神经元继发性隆起的假设来源。外周或中枢机制都可能导致自发性疼痛以及机械性和热性痛觉过敏/异常性疼痛。皮肤或肌肉中外周交感神经元和伤害感受器神经元之间的异常相互作用也仍然是神经病理性疼痛和痛觉过敏的理论机制。在过去的三十年里，我们的团队定期贡献关于精细结构，病理学，伤害感受器的正常和异常感觉功能以及交感神经单位的传出功能的事实科学知识，在患者和志愿者中。我们仍然从事神经性疼痛的临床和研究，最近开发了强大的方法，允许直接和同时的功能和生物物理特性和多种亚型的伤害感受器，热（冷）受体和交感神经单位的测试，同时观察可能的神经纤维相互作用。这是通过清醒人类的显微神经描记术和自动潜伏期跟踪（Qtrac）实现的。这些方法，通过对来自CRPS患者的DRG神经元胞体的体外研究补充，将用于测试CRPS中疼痛起源的3种假设：1）不同亚型的易激初级伤害感受器神经元通过异位神经冲动活动引起CRPS患者中的自发性疼痛和痛觉过敏/异常性疼痛，所述异位神经冲动活动由伤害感受器膜中特定离子通道的异常行为引起。2)作用于轴突和/或索马部位的交感神经传出放电可增加CRPS中的初级皮肤或深部组织伤害感受器活性，从而产生疼痛。3)冷痛觉过敏/异常性疼痛是CRPS中的一种突出症状，其归因于（a）伤害感受器传入中特定的有害低温膜受体的敏化，（B）伤害感受器传入中非有害冷却受体的异位表达，（c）有害冷信号输入的中枢释放，或（d）继发性中枢敏化。该项目的结果将证明或质疑神经性疼痛的相关假设机制，并将促进机制靶向治疗，同时保护CRPS患者免受医源性伤害。

DESCRIPTION (provided by applicant): Chronic neuropathic pains and hyperalgesias/allodynias following peripheral nerve or tissue insults, whether associated with nerve pathology (CRPS II) or not (CRPS I), curse patients, elude therapies and puzzle researchers. Hyperfunction of peripheral pain receptors (nociceptors) is an accepted cause of abnormal painful input in neuropathy (CRPSII) and a hypothetical source of secondary upheaval of pain-signaling neurons in the spinal cord, in CRPS I. Either peripheral or central mechanisms might account for spontaneous pains and for mechanical and thermal hyperalgesias/allodynias. Abnormal interaction between peripheral sympathetic and nociceptor neurons, in skin or muscle, also remains a theoretical mechanism of neuropathic pain and hyperalgesias. Over the past three decades our group has regularly contributed factual scientific knowledge about fine structure, pathology, and normal and abnormal sensory function of nociceptors and efferent function of sympathetic units, in patients and volunteers. We remain engaged in clinical and research studies on neuropathic pains and recently developed robust methods that allow direct and simultaneous functional and biophysical characterization and testing of multiple subtypes of nociceptors, thermal (cold) receptors and sympathetic units, while observing possible nerve fiber interactions. This is achieved through microneurography and automated latency tracking (Qtrac) in awake humans. These approaches, complemented by in vitro studies on DRG neuron somata from CRPS patients, will be used to test 3 hypotheses for the origin of pain in CRPS: 1) Irritable primary nociceptor neurons, of different subtypes, evoke spontaneous pains and hyperalgesias/allodynias in CRPS patients via ectopic nerve impulse activity, caused by abnormal behavior of particular ion channels in nociceptor membranes. 2) Sympathetic efferent discharge, acting at axonal and/or soma sites, may increase primary cutaneous or deep tissue nociceptor activity in CRPS, thus generating pains. 3) Cold hyperalgesia/allodynia, a prominent symptom in CRPS, is due to (a) sensitization of specific noxious low- temperature membrane receptors in nociceptor afferents, (b) ectopic expression of non-noxious cooling receptors in nociceptor afferents, (c) central release of noxious cold-signaling input, or (d) secondary central sensitization. Results of this project will prove, or question, pertinent hypothetical mechanisms of neuropathic pains and will facilitate mechanism-targeted therapy, while protecting CRPS patients from iatrogenic harm.