OPIOID GASTROINTESTINAL TOLERANCE AND DEPENDENCE

本项目旨在检验以下假设：(1)胃肠(G.I.)对阿片类药物依赖的耐受主要来自于脑内Mu阿片受体介导的药物作用和(2)胃肠道内Mu、Delta和Kappa阿片受体的药物作用。追踪有助于大脑中的依赖/戒断情况。这一假说是基于初步结果、当代对大脑-肠道双向相互作用的理解，以及阿片类药物耐受和依赖的现代概念。我们的初步数据显示，这种依赖可以在大兵身上表现出来。注射吗啡后未麻醉的大鼠的轨迹，这种依赖起源于大脑，而不是胃肠道。赛道。拟议的实验将扩大结果，包括详细检查中枢和外周给药后对多个终点的个别和汇总阿片类药物影响。具体地说，我们将通过持续评估对G.I.的耐受性来检验假设。在非麻醉大鼠脑内或外周输注受体选择性阿片类药物，然后将受体选择性拮抗剂注入大脑和/或外周，对运动的影响。我们还将评估特种部队。与急性阿片类药物效应、耐受性和戒断有关的推进、抗伤害性和行为。这些研究将提供一个新的阿片耐受/依赖的药理学结构，将主体因素、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.