MECHANISMS OF CAUSALGIA

描述(改编自申请人的摘要)这项提案的长期目标是揭示周围神经损伤后经常发生的致残性、痛苦的神经病理性疾病的潜在机制。在这一点上，中枢敏感化起着核心作用，而损伤传入的异位放电启动并维持这种中枢敏感化。因此，导致外周神经切断后异位放电的机制是至关重要的，因此也是本提案的主要焦点。一个潜在的假设是，如果了解了冲动产生的机制，就可以更好地控制它们，从而减少中枢敏感化，从而减少神经病理性疼痛。为了揭示异位冲动产生的机制，我们提出了四个具体的目标。第一个是证明异位放电存在一个与交感神经系统活动无关的基线成分和一个依赖于交感神经活动的附加成分。这将通过活体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起重要作用。这将通过体内和体外的电生理记录以及分子生物学和免疫组织化学技术来完成。第三个目标是使用与第二个目标相同的技术和假设，显示哪些亚型的肾上腺素能受体上调。第四个目的是确定嘌呤能和多肽能系统在异位放电产生中的作用。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使用对神经病大鼠异位放电的影响将使用电生理学和药理学技术进行检测。

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.