NGF-Dependent Sensitization of Nociceptors by Opiates

阿片类药物对伤害感受器的 NGF 依赖性敏化

基本信息

批准号：
7463076
负责人：
Frank Porreca
金额：
$ 34.8万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7463076
关键词：
Acute Address Affect Animals Area Behavior Behavioral Biological Blood C Fiber CALCA gene Calcitonin Gene-Related Peptide Capsaicin Cells Characteristics Chemicals Clinical Condition Data Development Dose Drug Formulations Exposure to Extravasation Fentanyl Fiber Fibers, A Fibromyalgia Filament Half-Life Human Hyperalgesia Hypersensitivity Immunofluorescence Immunologic Infusion procedures Injury Knockout Mice Lead Link MAP Kinase Gene MAPK14 gene Measures Mechanics Migraine Mitogen-Activated Protein Kinase Inhibitor Modality Molecular Morphine Nerve Growth Factor 1 Nerve Growth Factor Pathway Nervous system structure Neuraxis Neuronal Plasticity Neurons Nociceptors Opiates Opioid Opioid Receptor Pain Patients Peptides Peripheral Pharmaceutical Preparations Phosphorylation Plasma Process Public Health Rattus Reliance Reporting Role S100A12 gene Saline Skin Skin Tissue Spinal Spinal Ganglia Stimulus Substance P Substance Withdrawal Syndrome Surgical incisions TRPV1 gene Tactile Testing Time Tissues Transcriptional Regulation Transducers Up-Regulation Withdrawal Work allodynia central sensitization clinically significant concept day design dorsal horn enantiomer ganglion cell human S100A12 protein inhibitor/antagonist insight neurochemistry neuronal cell body osmotic minipump pre-clinical prevent research study response sciatic nerve subcutaneous trafficking

项目摘要

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.

描述（由申请人提供）：阿片类药物引起的痛觉过敏已在人类和动物中得到报道。连续几天服用阿片类药物会在周围和中枢神经系统中产生促伤害性神经塑性适应，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，但阿片类药物引起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“敏化”，从而增强对有害刺激和正常无害刺激的反应（即分别为痛觉过敏和异常性疼痛）。我们假设阿片引起的痛觉过敏和异常性疼痛可能是由于伤害感受器的敏化所致。重要的是，我们假设阿片类药物对伤害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感受器敏化？ 2) 阿片类药物引起的伤害感受器敏化是否部分是 NGF 依赖性过程的结果？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：阿片剂 (a) 作用于阿片剂受体，产生超敏反应并增加外周组织中 NGF 的表达； (b) 增加 TrkA 阳性细胞中 p38 MAPK (pp38 MAPK) 的 NGF 依赖性磷酸化，(c) 增加 TRPV1 通道至外周的 NGF 依赖性和 pp38 MAPK 依赖性运输，(d) 上调 CGRP 和 P 物质(SP) 以 NGF 依赖性和 pp38 MAPK 依赖性方式在 TrkA 阳性细胞中表达，并且 (e) 产生 NGF-、pp38 MAPK-和 TRPV1 依赖性超敏反应。公共卫生相关性：阿片类药物引起的神经可塑性的后果引发了这样的问题：是否真的会对患者造成意外伤害。鉴于普遍依赖阿片类药物来治疗严重疼痛，了解与长期接触这些药物相关的基本生物学机制至关重要。此外，在没有组织损伤的情况下发生的可能的伤害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着疼痛的临床状况的深入了解，包括例如纤维肌痛、IBS、CRPS-1和可能的偏头痛。阿片类药物引起的神经可塑性的后果引发了这样的问题：是否真的会对患者造成意外伤害。鉴于普遍依赖阿片类药物来治疗严重疼痛，了解与长期接触这些药物相关的基本生物学机制至关重要。此外，在没有组织损伤的情况下发生的可能的伤害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着疼痛的临床状况的深入了解，包括例如纤维肌痛、IBS、CRPS-1和可能的偏头痛。