Injury-Induced Pain: Chemical Modulation of Nociceptors

神经性疼痛状态的潜在机制尚未完全了解， 不太令人满意。我们小组进行的临床和实验研究表明，阿片类药物 减轻神经性疼痛。然而，使用全身性阿片类药物治疗疼痛受到其中枢神经系统的限制。 系统副作用，例如，镇静和认知功能障碍我们最近的报告和初步研究 表明外周μ阿片受体（莫尔）介导的机制可能在阿片类药物的作用中起作用。 神经病理性疼痛的镇痛。使用啮齿动物的L5脊神经结扎作为神经性疼痛的模型， 提出了研究外周MOR介导的镇痛，检查其机制， 确定增强外周MOR介导的镇痛是否会导致全身或鞘内 阿片类药物需求。特异性目标1将确定， 外周作用的莫尔激动剂在神经性疼痛中靠近初级传入神经的皮肤末梢， 沿着神经或背根神经节（DRG）的其它部位。行为研究将在神经性 在全身和足底内施用外周作用的莫尔激动剂之前和之后的动物， 洛哌丁胺具体目标2将使用免疫组织化学和分子生物学策略，以确定是否 L5脊神经损伤后初级传入神经元中的莫尔表达改变。我们假设L5 脊神经损伤导致L4 DRG中莫尔的代偿性上调， MORS外围。具体目标3将使用神经生理学技术来确定机制 外周作用的莫尔激动剂在神经性疼痛中的潜在作用。外围设备的影响 阿片类药物对初级传入伤害性感受器反应特性的影响及中枢神经系统的维持 将研究神经损伤后脊髓背角细胞的敏化。具体目标4将检查是否 局部注射重组单纯疱疹病毒引起初级传入神经中MORs的过度表达 载体可用作治疗神经性疼痛的策略。我们将调查是否增加 初级传入纤维上的莫尔表达将导致吗啡镇痛剂量-反应曲线的显著偏移。 外周、鞘内和全身阿片样激动剂。拟议的研究应提供新的见解， 阿片类药物对神经病理性疼痛的外周抗痛觉过敏作用的机制， 新的治疗策略。

The mechanisms underlying neuropathic pain states are not completely understood, and therapeutic options are less than satisfactory. Clinical and experimental studies conducted by our group indicate that opioids attenuate neuropathic pain. The use of systemic opioids for pain, however, is limited by their central nervous system side effects, e.g., sedation and cognitive dysfunction. Recent reports and preliminary studies by our group indicate that peripheral u-opioid receptor (MOR) mediated mechanisms may play a role in opioid analgesia in neuropathic pain. Using L5 spinal nerve ligation in rodents as a model of neuropathic pain, studies are proposed to characterize peripheral MOR-mediated analgesia, examine its mechanisms, and determine if enhancing peripheral MOR-mediated analgesia will lead to a decrease in systemic or intrathecal opioid requirements. Specific Aim 1 will determine if the site of action for the antihyperalgesic effects of peripherally acting MOR agonists in neuropathic pain is near cutaneous terminals of primary afferentsor at other sites along the nerve or dorsal root ganglia (DRG). Behavioral studies will be performed in neuropathic animals before and after systemic and intraplantar administration of the peripherally acting MOR agonist, loperamide. Specific Aim 2 will use immuno-histochemical and molecular biological strategies to determine if MOR expression in primary afferent neurons is altered after L5 spinal nerve injury. We postulate that L5 spinal nerve injury results in compensatory upregulation of MOR in the L4 DRG and increased transport of MORs to the periphery. Specific aim 3 will use neurophysiologic techniques to determine the mechanisms underlying the effects of peripherally acting MOR agonists in neuropathic pain. The effects of peripheral opioids on the response properties of primary afferent nociceptors and the maintenance of central sensitization of spinal dorsal horn cells after nerve injury will be studied. Specific Aim 4 will examine if overexpression of MORs in primary afferents by topical administration of recombinant herpes simplex viral vectors can be used as a strategy for the treatment of neuropathic pain. We will investigate if increasing the MOR expression on primary afferents will lead to a leftward shift in the analgesic dose-response curves of peripheral, intrathecal, and systemic opioid agonists. The proposed studies should provide new insights into the mechanisms of the peripheral antihyperalgesic effects of opioids on neuropathic pain and should lead to novel therapeutic strategies.