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/异常性痛，无论是否与神经病理（CRPS II）相关（CRPS I），诅咒患者，逃避治疗和困扰研究人员。外周疼痛感受器（痛觉感受器）功能亢进是神经病变（CRPSII）中疼痛输入异常的公认原因，也是CRPS i中脊髓疼痛信号神经元继发性剧变的假设来源。外周或中枢机制都可能解释自发性疼痛以及机械性和热性痛觉过敏/异常性痛。皮肤或肌肉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是神经性疼痛和痛觉过敏的理论机制。在过去的三十年中，我们的团队在患者和志愿者中定期贡献有关伤害感受器的精细结构，病理，正常和异常的感觉功能以及交感神经单位的传出功能的事实科学知识。我们继续从事神经性疼痛的临床和研究，最近开发了强大的方法，可以直接和同时对伤害感受器、热（冷）感受器和交感神经单位的多种亚型进行功能和生物物理表征和测试，同时观察可能的神经纤维相互作用。这是通过微神经造影和清醒人类的自动延迟跟踪（Qtrac）来实现的。这些方法，结合体外对CRPS患者DRG神经元体的研究，将用于验证3种关于CRPS疼痛起源的假设：1)不同亚型的易激初级伤害感受器神经元，通过伤害感受器膜中特定离子通道的异常行为引起的神经冲动活动异位，引起CRPS患者自发性疼痛和痛觉过敏/异常性痛。2)交感神经传出放电作用于轴突和/或躯体部位，可增加CRPS中原发性皮肤或深层组织伤害感受器的活性，从而产生疼痛。3)冷痛觉过敏/异位性痛是CRPS的一个突出症状，是由于(a)伤害感受器传入的特定有害低温膜受体致敏，(b)伤害感受器传入的非有害冷却受体异位表达，(c)有害冷信号输入的中枢释放，或(d)继发性中枢致敏。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.