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Opioid and Non-Opioid Actions of Dynorphin in Pain

强啡肽在疼痛中的阿片类和非阿片类药物作用

基本信息

批准号：
6846571
负责人：
Frank Porreca
金额：
$ 41.07万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-01 至 2006-01-31
项目状态：
已结题

项目摘要

DESCRIPTION:(from applicant's abstract): One of the most significant health problems in our country is the inadequate treatment of pain, especially the chronic abnormal pains often associated with nerve injury (neuropathic pain). Injuries to nerves in experimental models of neuropathic pain elicit peripheral, spinal and supraspinal neural plasticity characterized in part by increased expression of spinal dynorphin. Progress made in our previous funding period suggests that enhanced expression of dynorphin resulting from experimental nerve injury acts in a non-opioid fashion to promote pain. Some of the relevant observations which support a pronociceptive role of dynorphin in the post-nerve injury state include: (a) spatial and temporal correlation of increased spinal dynorphin expression across multiple, anatomically relevant spinal segments following nerve injury, (b) inhibition of nerve-injury induced pain by antiserum to dynorphin, but not control serum, and (c) demonstration of sustained nerve-injury induced pain in wild-type (WT), but not in prodynorphin "knock-out" (KO) mice. Our studies show that dynorphin (2-17) (which does not bind to opioid receptors) promotes calcium accumulation in DRG cells in culture and activates protein kinase C (PKC) in spinal cord. Moreover, des-Tyr fragments of dynorphin enhance capsaicin-stimulated CGRP release in DRG cells and in spinal cord tissue preparations. The overall hypothesis of our work is that spinal dynorphin is pronociceptive and it a critical mediator which serves to maintain pathological post-nerve injury pain. Specifically we propose a mechanism by which dynorphin maintains post-nerve injury pain by increasing spinal excitability, in part, by enhancing the release of excitatory transmitters. Our aims are designed to systematically test this hypothesized mechanism. Aim 1 will determine whether nerve-injury induced changes in dynorphin expression are the result of modulatory influences from supraspinal sites. Aim 2 will focus on measurement of nerve-injury induced release of dynorphin at the spinal level. Aim 3 will use cultured DRG cells to test if dynorphin enhances evoked CGRP release through activation of PKC. Aim 4 will use spinal cord tissue preparations taken from sham- or nerve-injured rats, as well as from sham- or nerve-injured WT and prodynorphin KO mice to determine the role of endogenous, pathological levels of dynorphin on basal and evoked CGRP release. Aim 5 will focus on the role of dynorphin in the release of excitatory amino acids in sham-operated and nerve-injured rats. The experiments in Aim 5 will be carried out in the laboratory of Dr. Tony Yaksh through a Consortium Arrangement. All of these studies focus on the central hypothesis of pronociceptive actions of dynorphin in the post nerve-injury state and test a proposed mechanism which addresses how dynorphin may act under conditions of nerve-injury to maintain pain. As most clinical conditions of neuropathic pain are treated in the post-injury (i.e., maintenance) state, such information may allow approaches to limit or reverse the pathological actions of dynorphin in maintaining neuropathic pain.

描述：(摘自申请人的摘要)：我国最大的健康问题之一是营养不足。疼痛的治疗，尤指常伴有的慢性反常疼痛神经损伤(神经病理性疼痛)。实验性脑损伤模型中的神经损伤神经病理性疼痛引起外周、脊髓和棘上神经可塑性部分特征是脊髓强啡肽表达增加。进展在我们之前的资助期所做的工作表明，实验性神经损伤导致的强啡肽以非阿片类药物的方式发挥作用来促进疼痛。一些相关的观察结果支持强啡肽在神经损伤后状态中的致痛作用包括：(A) 脊髓强啡肽表达增强的时空相关性在神经损伤后跨越多个解剖学上相关的脊柱节段， (B)强啡肽抗血清抑制神经损伤引起的疼痛，但不是对照血清，和(C)显示持续的神经损伤引起的疼痛野生型(WT)，但不存在前强啡肽“敲除”(KO)小鼠。我们的研究表明强啡肽(2-17)(不与阿片受体结合)促进培养的背根神经节细胞内钙蓄积并激活蛋白激酶C (PKC)。此外，强啡肽的Des-Tyr片段增强了辣椒素刺激背根节细胞和脊髓组织中CGRP的释放准备工作。我们工作的总体假设是脊髓强啡肽是它是一种关键的介质，用来维持病理状态神经损伤后疼痛。具体地说，我们提出了一种强啡肽的机制通过增加脊髓兴奋性来维持神经损伤后的疼痛，部分是通过促进兴奋性递质的释放。我们的目标是系统地测试这一假设的机制。目标1将决定是否神经损伤引起的强啡肽表达的变化是来自棘上部位的调制影响。目标2将专注于测量神经损伤导致脊髓水平强啡肽的释放。目标3将用培养的背根节细胞检测强啡肽是否促进CGRP的释放通过激活PKC。AIM 4将使用所采集的脊髓组织制剂来自假损伤或神经损伤的大鼠，以及来自假或神经损伤的WT和测定前强啡肽在KO小鼠内源性、病理水平上的作用强啡肽对基础和诱发CGRP释放的影响。目标5将重点放在强啡肽在假手术和大鼠兴奋性氨基酸释放中的作用神经损伤的大鼠。目标5中的实验将在托尼·雅克什博士的实验室通过财团安排。所有这些都是研究集中在强啡肽致痛作用的中枢假说上在神经损伤后状态下并测试提出的机制，该机制解决了强啡肽如何在神经损伤的情况下维持疼痛。AS 大多数神经病理性疼痛的临床症状是在损伤后治疗的。 (即，维护)状态，这样的信息可以允许采用限制或逆转强啡肽维持神经病理性疼痛的病理作用。