INJURY-INDUCES PAIN-- CHEMICAL MODULATION OF NOCICEPTORS

神经性疼痛的机制尚不完全清楚。这项资助将检查周围神经损伤后周围和中枢神经系统发生的变化。对神经性疼痛患者的心理物理研究将辅以行为和电生理研究，在一个明确定义的神经性疼痛模型中，涉及大鼠L5脊神经的结扎，以及小鼠特定蛋白质的突变。前两个特定的目的集中在肾上腺素能敏感性的皮肤发展的神经性疼痛患者的一个亚群，是维持在交感神经传出纤维的活动（交感神经维持疼痛，SMP）。在之前的资助期间，皮内注射去甲肾上腺素被发现在SMP患者中产生剂量依赖性疼痛，这表明在这种疾病中皮肤伤害感受器对肾上腺素产生敏感性。在即将到来的资助期内，去甲肾上腺素离子导入将作为一种新的、无创的SMP诊断测试进行测试（Sp. Aim 1）。此外，将通过测量选择性肾上腺素能激动剂和拮抗剂皮肤离子导入后疼痛的变化来研究SMP的肾上腺素能受体药理学（Sp. Aim 2）。神经性疼痛的患者特别痛苦的疼痛引起通常无害的机械刺激。一系列的实验将集中在确定痛觉传入纤维和低阈值机械感受器（LTMs）在神经性动物痛觉过敏信号传导中的不同作用。将使用神经毒素辣椒素（Sp. Aim 3）研究伤害感受器功能选择性丧失的影响，并使用小鼠特异性神经营养因子突变体（Sp. Aim 4）研究ltm的选择性消耗。最后两个具体的目的集中在机制增加兴奋性的脊髓背角，发展后的神经损伤。这种背角致敏可能是由于兴奋机制的增加或抑制机制的减少。在即将到来的资助期间，将通过研究神经激肽（NK）受体系统对脊髓伤害性传递的调节作用来探索兴奋机制的变化（Sp. Aim 5）。抑制机制的变化将通过研究阿片受体系统的调节作用来探索（Sp. Aim 6）。选择性NK拮抗剂的药理学和神经生理学研究将用于确定NK受体是否在神经性疼痛中上调。此外，将在NK-1受体和mu-阿片受体敲除小鼠中检测疼痛行为和背角生理学。这些研究结果将为神经性疼痛的外周和中枢机制提供新的见解，并可能导致新的诊断和治疗策略。

The mechanisms underlying neuropathic pain remain incompletely understood. This grant will examine changes that occur in both the peripheral and central nervous system after a peripheral nerve injury. Psychophysical studies in patients with neuropathic pain will be complemented by behavioral and electrophysiological studies in a well-defined model of neuropathic pain that involves ligation of the L5 spinal nerve in rats, and in mice mutant for specific proteins. The first two specific aims focus on the adrenergic sensitivity that develops in the skin of a subset of patients with neuropathic pain that is maintained by activity in sympathetic efferent fibers (sympathetically maintained pain, SMP). During the previous grant period, intradermal injections of norepinephrine were found to produce a dose-dependent pain in patients with SMP, suggesting that cutaneous nociceptors develop a sensitivity to adrenaline in this disease. During the coming grant period, norepinephrine iontophoresis in patients with and without SMP will be tested as a new, non-invasive, diagnostic test for SMP (Sp. Aim 1). In addition, the adrenoceptor pharmacology of SMP will be investigated by measuring the alterations in pain following the cutaneous iontophoresis of selective adrenergic agonists and antagonists (Sp. Aim 2). Patients with neuropathic pain are particularly distressed by the pain evoked by normally innocuous mechanical stimuli. A series of experiments will focus on determining the differential role of nociceptive afferent fibers and low-threshold mechanoreceptors (LTMs) in signaling the hyperalgesia in neuropathic animals. The effects of selective loss of nociceptor function will be investigated using the neurotoxin, capsaicin (Sp. Aim 3), and selective depletion of LTMs will be examined by use of mice mutant for specific neurotrophic factors (Sp. Aim 4). The final two specific aims focus on the mechanisms of increased excitability of the spinal dorsal horn that develops following a nerve injury. This dorsal horn sensitization could be due to either an increase in excitatory mechanisms or a decrease in inhibitory mechanisms. During the coming grant period, changes in excitatory mechanisms will be explored by investigating the modulatory effects of neurokinin (NK) receptor systems on nociceptive transmission in the spinal cord (Sp. Aim 5). Changes in inhibitory mechanisms will be explored by investigating the modulatory effects of opioid receptor systems (Sp. Aim 6). Pharmacological and neurophysiological studies with selective NK antagonists will be used to determine if the NK receptors are upregulated in neuropathic pain. In addition, pain behavior and dorsal horn physiology will be examined in NK-1 receptor and mu-opioid receptor knockout mice. The results of these studies should provide new insights into the peripheral and central mechanisms of neuropathic pain and may lead to novel diagnostic and therapeutic strategies.