MECHANISMS OF CAUSALGIA

描述（改编自申请人的摘要）本提案的长期目标是揭示经常伴随周围神经损伤的致残性、疼痛性神经性疾病的机制。在这方面，中枢敏化起着核心作用，并且来自受损传入神经的异位放电启动并维持这种中枢敏化。因此，机制，导致异位放电后外周神经切断术是至关重要的，因此，本建议的主要焦点。一个潜在的假设是，如果了解冲动产生的机制，它们可以更好地控制，从而减少中枢敏感化，从而减少神经性疼痛。提出了四个具体的目标，以解开异位冲动产生的机制。第一个是表明，有一个基线组件的异位放电是独立的交感神经系统的活动和一个附加组件，是依赖于交感神经活动。这将通过体内单个背根纤维记录来显示。第二个目的是显示哪些钠通道亚型在神经损伤后上调，假设上调的通道在冲动产生中是重要的。这将通过体内和体外电生理记录以及分子生物学和免疫组织化学技术来完成。第三个目的是显示肾上腺素能受体的哪些亚型被上调，使用与第二个目的相同的技术和假设。第四个目的是确定嘌呤能和肽能系统在异位放电产生中的作用。将使用电生理学和药理学技术检查ATP和神经肽Y的激动剂和拮抗剂单独或与肾上腺素能药物联合给药对神经病大鼠异位放电的影响。

DESCRIPTION (Adapted from the applicant's abstract) The long term goal of this proposal is to uncover mechanisms that underlie the disabling, painful neuropathic disease that often follows peripheral nerve injuries. In this regard, central sensitization plays a central role, and ectopic discharges from injured afferents initiate and maintain this central sensitization. Accordingly, the mechanisms that lead to ectopic discharges following peripheral axotomy are critically important and are thus the main focus of this proposal. An underlying hypothesis is that, if the mechanisms of impulse generation are understood, they can be better controlled, with a resultant reduction in central sensitization and thus in neuropathic pain. Four specific aims are proposed to unravel the mechanisms of ectopic impulse generation. The first is to show that there is a baseline component of ectopic discharge that is independent of activity in the sympathetic nervous system and an additive component that is dependent on sympathetic activity. This will be shown by in-vivo single dorsal root fiber recordings. The second aim is to show which sodium channel subtypes are up-regulated after nerve lesions, the assumption being that the up-regulated channels are important in impulse generation. This will be done with in-vivo and in-vitro electrophysiological recordings and molecular biological and immunohistochemical techniques. The third aim is to show which subtypes of adrenergic receptors are up-regulated, using the same techniques and assumptions as the second aim. The fourth aim is to determine the roles of purinergic and peptidergic systems in the generation of ectopic discharges. The effects of agonists and antagonists for ATP and neuropeptide Y, given either alone or in conjunction with adrenergic agents, on ectopic discharges in neuropathic rats will be examined using electrophysiological and pharmacological techniques.