OPIOID GASTROINTESTINAL TOLERANCE AND DEPENDENCE

本项目旨在验证以下假设：（1）胃肠道（g.i.）对阿片类药物依赖的耐受性主要来自脑中μ阿片受体介导的药物作用和（2）胃肠道中μ、δ和κ阿片受体的药物作用。跟踪有助于大脑中的依赖/戒断特征。该假说基于初步结果，对双向脑肠相互作用的当代理解以及阿片类药物耐受性和依赖性的现代概念。我们的初步数据表明，依赖性可以在胃肠道中得到证明。跟踪未麻醉大鼠输注吗啡后，依赖性起源于大脑，而不是在g.i.轨道拟定实验将扩展结果，以包括详细检查中枢和外周给药后阿片类药物对多个终点的个体和总和效应。具体而言，我们将通过持续评估对g.i.的耐受性来检验假设。在向未麻醉大鼠的脑或外周输注期间，对受体选择性阿片类药物的运动性影响，随后向脑和/或外周给予受体选择性拮抗剂。我们还将评估G.I.推进、抗伤害感受和与急性阿片样物质作用、耐受和戒断相关的行为。这些研究将为阿片类药物耐受/依赖提供一个新的药理学结构，将受试者因素、药物因素、控制因素和功能因素联系起来。

This project is designed to test the hypothesis that (1) gastrointestinal (g.i.) Tolerance to an dependence upon opioid drugs result primarily from drug actions mediated by mu opioid receptors in the brain and (2) drug actions at mu, delta and kappa opioid receptors in the g.i. track contribute to the dependence/withdrawal profile in the brain. The hypothesis is based upon preliminary results, contemporary understanding of bi-directional brain-gut interactions, and modern concepts of opioid tolerance and dependence. Our preliminary data show that dependence can be demonstrated in the g.i. track of unanesthetized rats after infusion of morphine and that the dependence originates in the brain, not in the g.i. track. The proposed experiments will extend the results to include detailed examination of individual and summated opioid effects on multiple endpoints after central and peripheral administration. Specifically, we will test the hypothesis by continuous evaluation of tolerance to g.i. motility effects on receptor-selective opioids during infusion into the brain or periphery in unanesthetized rats, followed by administration of receptor-selective antagonists into the brain and/or periphery. We will also assess g.i. propulsion, antinociception, and behavior relevant to acute opioid effects, tolerance, and withdrawal. These studies will provide a new pharmacological construct of opioid tolerance/dependence that links subject factors, drug factors, control factors, and functional factors.