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：
8215873
负责人：
Frank Porreca
金额：
$ 32.37万
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 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215873
关键词：
Acute Address Affect Animals Area Behavior Behavioral Biological Blood C Fiber Capsaicin Cells Characteristics Chemicals Clinical Complex Regional Pain Syndromes Data Development Dose Drug Formulations Exposure to Extravasation Fentanyl Fiber Fibromyalgia Filament Half-Life Health 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 Nervous system structure Neuraxis Neuronal Plasticity Neurons Nociceptors Opiates Opioid Opioid Receptor Pain Patients Peptides Peripheral Pharmaceutical Preparations Phosphorylation Plasma Process Rattus Reliance Reporting Role 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 design dorsal horn enantiomer ganglion cell 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）：鸦片诱发的痛觉过敏已在人类和动物中报道。连续的鸦片施用几天在周围和中枢神经系统中产生引起的神经塑性适应，这可能是观察到的超敏反应的基础。尽管这种变化具有潜在的临床意义，但鸦片诱发的超敏反应的特定机制尚不清楚。对组织的损伤可能导致伤害感受器的敏感性}，从而增强对有害和通常无毒性刺激的反应（即分别是痛苦和异常性刺激）。我们假设鸦片诱发的痛觉过敏和异常性症可能是由于伤害感受器的敏化而引起的。重要的是，我们假设在没有组织损伤的情况下，可以通过阿片类药物对伤害感受器的敏化。本应用程序提出的实验解决了两个具体问题：1）阿片类药物可以在没有组织损伤的情况下引起伤害感受器的敏化吗？ 2）鸦片诱导的伤害感受器的敏化是否部分依赖于NGF的过程？行为，神经化学，免疫组织化学和电生理研究将检验（a）在阿片受体上作用（a）的假设，以产生过敏性和外周组织中NGF表达的增加。（b）增加TRKA阳性细胞中p38 MAPK（PP38 MAPK）的NGF依赖性磷酸化，（c）（c）增加TRPV1通道对外围的trpv1通道的NGF依赖性和PP38 MAPK依赖性运输，（d）上调CGRP和P（d）在Trka阳性细胞中的表达，并依赖于trka阳性细胞，并依赖于ngs阳性的细胞，并依赖于p3 （e）产生NGF-，PP38 MAPK-和TRPV1依赖性超敏反应。公共卫生相关性：鸦片引起的神经可塑性的后果引起了问题，即是否可能对患者发生意外伤害。鉴于人们普遍依赖阿片类药物治疗严重疼痛，因此了解与长期接触这些药物相关的基本生物学机制是必不可少的。另外，在没有组织损伤的情况下发生可能的伤害感受器敏化的机制最终可能会导致对显着疼痛的临床状况的见解，而没有明显的组织损伤，包括纤维肌痛，IBS，CRPS，CRPS-1，也许是偏头痛。鸦片引起的神经塑性的后果引发了问题，即是否可能实际上会对患者造成意外伤害。鉴于人们普遍依赖阿片类药物治疗严重疼痛，因此了解与长期接触这些药物相关的基本生物学机制是必不可少的。另外，在没有组织损伤的情况下发生可能的伤害感受器敏化的机制最终可能会导致对显着疼痛的临床状况的见解，而没有明显的组织损伤，包括纤维肌痛，IBS，CRPS，CRPS-1，也许是偏头痛。