AGE-RELATED DIFFERENCES IN OPIOID SENSITIVITY

阿片类药物滥用研究的一个主要目标是确定导致阿片类药物滥用的各种生物学、药理学和情境因素。这项研究的一个重要组成部分是检查不同受试者群体对阿片类药物敏感性的差异。这项研究表明，不同年龄段的人对阿片类药物的敏感性往往不同。尽管造成这些差异的机制尚不完全清楚，但有数据表明，与年龄相关的阿片受体生理改变可能起作用。这种改变可能会影响个体对阿片类药物的反应，并可能导致受试者群体中阿片类药物敏感性的巨大差异。本研究项目的目的是研究在温水断尾过程中，mu阿片类药物对抗痛觉（即镇痛）作用的敏感性与年龄相关的差异。在这个过程中，大鼠被限制，并记录从50和55℃的水中去除尾巴的潜伏期。在实验一中，我们将在幼龄大鼠（3个月）、成熟大鼠（12个月）和老年大鼠（24个月）中检测几种mu阿片类药物的抗伤害感受作用。本实验的目的是量化对mu类阿片抗痛觉作用敏感性的年龄相关差异，并确定这些差异是否受到痛觉刺激强度（即水温）和/或测试药物的内在功效（即其与受体位点结合后启动细胞反应的能力）的影响。在实验二中，将研究三个年龄组对mu阿片类药物的耐受性和交叉耐受性的发展。在尾戒断过程中，将在慢性吗啡给药（20mg /kg b.i.d）之前和期间检查几种mu阿片类药物的抗痛觉作用。本实验的目的是量化与年龄相关的阿片类药物耐受性发展速度和程度的差异，并确定这些差异是否受到阿片类药物内在功效的影响。

A major goal of opioid abuse research is to identify the various biological, pharmacological and situational factors that contribute to opioid abuse. One important component of this research involves examining differences in opioid sensitivity across subject populations. This research has shown that sensitivity to the effects of opioids often differs across age groups. Although the mechanisms responsible for these differences are not fully understood, there are data indicating that age-related alterations in opioid receptor physiology may play a role. Such alterations may influence an individual's response to opioids, and may result in large differences in opioid sensitivity across subject populations. The purpose of this research project is to examine age-related differences in sensitivity to the antinociceptive (i.e., analgesic) effects of mu opioids in the warm-water, tail-withdrawal procedure. In this procedure, rats are restrained and the latencies to remove their tails from 50 and 55 C water are recorded. In experiment I, the antinociceptive effects of several mu opioids will be examined in young (3 months), mature, (12 months) and aged (24 months) rats. The aim of this experiment is to quantify age- related differences in sensitivity to the antinociceptive effects of mu opioids, and to determine if these differences are influenced by the intensity of the nociceptive stimulus (i.e., water temperature) and/or the intrinsic efficacy of the test drug (i.e., its ability to initiate a cellular response after binding to its receptor site). In experiment II, the development of tolerance and cross-tolerance to the effects of mu opioids will be examined across the three age groups. In the tail-withdrawal procedure, the antinociceptive effects of several mu opioids will be examined before and during a regimen of chronic morphine administration (20 mg/kg b.i.d.). The aim of this experiment is to quantify age-related differences in the speed and magnitude to which tolerance develops to the effects of mu opioids, and to determine if these differences are influenced by an opioid's intrinsic efficacy.