NGF-Dependent Sensitization of Nociceptors by Opiates

描述(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。持续几天的阿片类药物给药会在外周和中枢神经系统产生伤害性神经可塑性适应，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，但阿片类药物诱导的超敏反应的具体机制尚不清楚。对组织的损伤可导致伤害性感受器的敏化，导致对伤害性刺激和正常非伤害性刺激(分别为痛觉过敏和超感痛觉)的反应增强。我们推测，阿片类药物引起的痛觉过敏和痛觉过敏可能是痛觉感受器敏化的结果。重要的是，我们假设阿片类药物对伤害性感受器的敏化可以在没有组织损伤的情况下发生。本申请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性感受器敏化？2)阿片类药物诱导的伤害性感受器敏化是否部分是NGF依赖过程的结果？行为、神经化学、免疫组织化学和电生理学研究将检验以下假设：阿片类药物(A)作用于阿片受体，产生超敏反应并增加周围组织中NGF的表达；(B)增加TrkA阳性细胞中NGF依赖的p38 MAPK(Pp38 MAPK)的磷酸化，(C)增加NGF依赖和pp38 MAPK依赖的TRPV1通道向外周的转运，(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：鸦片类药物诱导的神经可塑性的后果引发了是否真的会对患者造成意外伤害的问题。鉴于严重疼痛的治疗普遍依赖阿片类药物，了解与长期接触这些药物有关的基本生物学机制是至关重要的。此外，在没有组织损伤的情况下可能发生的伤害性感受器敏化的潜在机制可能最终导致对没有明显组织损伤的显著疼痛的临床情况的洞察，例如纤维肌痛、IBS、CRPS-1以及可能的偏头痛。阿片剂诱导的神经可塑性的后果提出了一个问题，即是否真的会发生对患者的意外伤害。鉴于严重疼痛的治疗普遍依赖阿片类药物，了解与长期接触这些药物有关的基本生物学机制是至关重要的。此外，在没有组织损伤的情况下可能发生的伤害性感受器敏化的潜在机制可能最终导致对没有明显组织损伤的显著疼痛的临床情况的洞察，例如纤维肌痛、IBS、CRPS-1以及可能的偏头痛。

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.