NGF-Dependent Sensitization of Nociceptors by Opiates

描述（由申请人提供）：阿片类药物引起的痛觉过敏在人类和动物中都有报道。连续几天服用阿片类药物会在周围和中枢神经系统产生前感觉神经可塑性适应，这可能是观察到的超敏反应的基础。尽管这些变化具有潜在的临床意义，但阿片诱导的超敏反应的具体机制尚不清楚。组织损伤可导致伤害感受器的致敏，导致对有害和通常无害刺激的反应增强（分别为痛觉过敏和异常性痛觉）。我们假设阿片类药物引起的痛觉过敏和异常痛觉可能是由伤害感受器致敏引起的。重要的是，我们假设阿片类药物对伤害感受器的致敏可以在没有组织损伤的情况下发生。本应用中提出的实验解决了两个具体问题：1)阿片类药物能否在不损伤组织的情况下诱导伤害感受器致敏？2)阿片类药物诱导的伤害感受器致敏在一定程度上是ngf依赖性过程的结果吗？行为学、神经化学、免疫组织化学和电生理研究将检验阿片(a)作用于阿片受体产生超敏反应和外周组织中神经生长因子表达增加的假设；(b)增加trka阳性细胞中NGF依赖的p38 MAPK磷酸化（pp38 MAPK）， (c)增加NGF依赖和pp38 MAPK依赖的TRPV1通道向外周的运输，(d)以NGF依赖和pp38 MAPK依赖的方式上调trka阳性细胞中CGRP和P物质（SP）的表达，以及(e)产生NGF-， pp38 MAPK和TRPV1依赖的超敏反应。公共卫生相关性：阿片类药物诱导的神经可塑性的后果引发了对患者是否可能发生意外伤害的问题。鉴于普遍依赖阿片类药物治疗严重疼痛，了解与长期暴露于这些药物相关的基本生物学机制是必不可少的。此外，在没有组织损伤的情况下，伤害感受器致敏的潜在机制可能最终导致对无明显组织损伤的显著疼痛的临床状况的深入了解，例如纤维肌痛、肠易激综合征、CRPS-1和偏头痛。阿片类药物诱导的神经可塑性的后果引发了一个问题，即对患者的意外伤害是否真的会发生。鉴于普遍依赖阿片类药物治疗严重疼痛，了解与长期暴露于这些药物相关的基本生物学机制是必不可少的。此外，在没有组织损伤的情况下，伤害感受器致敏的潜在机制可能最终导致对无明显组织损伤的显著疼痛的临床状况的深入了解，例如纤维肌痛、肠易激综合征、CRPS-1和偏头痛。

DESCRIPTION (provided by applicant): Opiate-induced hyperalgesia has been reported in humans and in animals. Continuous opiate administration for several days produces pronociceptive neuroplastic adaptations in both the peripheral and central nervous systems which likely underlie the observed hypersensitivity. Despite the potential clinical significance of such changes, specific mechanisms of opiate- induced hypersensitivity are unknown. Injury to tissues can result in }sensitization} of nociceptors, resulting in enhanced response to noxious and normally non-noxious stimuli (i.e., hyperalgesia and allodynia, respectively). We hypothesize that opiate-induced hyperalgesia and allodynia may result from sensitization of nociceptors. Importantly, we hypothesize that sensitization of nociceptors by opiates can occur in the absence of tissue injury. Two specific questions are addressed by the experiments proposed in this application: 1) can opiates induce nociceptor sensitization without tissue injury? 2) is opiate-induced nociceptor sensitization the result, in part, of an NGF-dependent process? Behavioral, neurochemical, immunohistochemical and electrophysiological studies will test the hypothesis that opiates (a) act at opiate receptors to produce hypersensitivity and an increase in expression of NGF in peripheral tissues; (b) increase NGF-dependent phosphorylation of p38 MAPK (pp38 MAPK) in TrkA-positive cells, (c) increase NGF-dependent and pp38 MAPK-dependent trafficking of the TRPV1 channel to the periphery, (d) upregulate CGRP and substance P (SP) expression in TrkA-positive cells in an NGF-dependent, and pp38 MAPK-dependent fashion, and (e) produce NGF-, pp38 MAPK- and TRPV1-dependent hypersensitivity. PUBLIC HEALTH RELEVANCE: The consequences of opiate-induced neuroplasticity raise questions of whether unintended harm to patients might actually occur. Given the prevalent reliance on opiates for treatment of severe pain, understanding of the fundamental biological mechanisms associated with prolonged exposure to these drugs is essential. Additionally, mechanisms underlying possible nociceptor sensitization occurring in the absence of tissue injury may ultimately lead to insights into clinical conditions of prominent pain without apparent tissue injury including, for example fibromyalgia, IBS, CRPS-1 and perhaps migraine. The consequences of opiate-induced neuroplasticity raise questions of whether unintended harm to patients might actually occur. Given the prevalent reliance on opiates for treatment of severe pain, understanding of the fundamental biological mechanisms associated with prolonged exposure to these drugs is essential. Additionally, mechanisms underlying possible nociceptor sensitization occurring in the absence of tissue injury may ultimately lead to insights into clinical conditions of prominent pain without apparent tissue injury including, for example fibromyalgia, IBS, CRPS-1 and perhaps migraine.