TOLERANCE TO MORPHINE ANALGESIA--BIOBEHAVIOR FACTORS

描述：申请人摘要 目前的建议旨在利用基础动物研究来了解 行为和生物学因素对镇痛作用的相对贡献 临床环境中的耐受性。 我们建议将 吗啡镇痛耐受性形成的机制 通过测试疼痛时“压力触发”变化的假设， 影响吗啡的治疗作用。 更具体地说，我们 提出疼痛对吗啡耐受性发展的影响 镇痛依赖于疼痛时皮质酮的活性。 我们将测试这个 假设在大鼠模型中，近似阿片类药物的临床使用， 疼痛控制，我们最近发现， 吗啡不产生镇痛耐受性时，管理在 疼痛的存在，但没有疼痛。 确定的作用 皮质酮在吗啡镇痛耐受性形成中的作用 痛苦我们将建立一个痛苦之间的关系，宽容和 皮质酮活性 我们的假设预测， 阻断疼痛触发的皮质酮活动将阻止这种阻断 对痛苦的忍耐。 此外，我们还将与 疼痛触发的皮质酮活动的应变差异， 在疼痛期间对吗啡镇痛的耐受性的发展。 我们的假设 预测，一种被鉴定为缺乏典型的应激诱导的大鼠品系， 内分泌反应（刘易斯品系）不会显示出 皮质酮后疼痛，因此不会显示出封锁， 忍受痛苦。 该提案还将评估生物行为 通过检查影响疼痛耐受性发展的因素 疼痛类型、皮质酮和吗啡给药方式对镇痛效果影响 局 我们将研究疼痛减弱的条件 耐受性与疼痛不能削弱耐受性的条件。 我们 这一假说预测疼痛和皮质酮对耐受性的影响 发展可以预测的基础上存在或不存在的 与吗啡给药有关的环境线索。 的 确定影响的生物和行为因素 疼痛期间对吗啡镇痛的耐受性将提供对 在临床上决定ape耐受性发展的机制 设置.

DESCRIPTION: Applicant's Abstract The present proposal is aimed at using basic animal research to understand the relative contribution of behavioral and biological factors to analgesic tolerance in the clinical setting. We propose to characterize the mechanisms that underlie the development of tolerance to morphine analgesia by testing the hypothesis that "stress-triggered" changes during pain influence the therapeutic actions of morphine. More specifically, we propose that the effects of pain on the development of tolerance to morphine analgesia depends on corticosterone activity during pain. We will test this hypothesis in a rat model that approximates the clinical use of opiates for pain control, in which we recently showed that repeated injections of morphine do not produce analgesic tolerance when administered in the presence of pain, but do in the absence of pain. To determine the role of corticosterone in the development of tolerance to morphine analgesia during pain we will establish a relationship between the pain, tolerance and corticosterone activity. Our hypothesis predicts that pharmacological blockade of pain-triggered corticosterone activity will prevent the blockade of tolerance by pain. In addition, we will establish a relationship between strain differences in pain-triggered corticosterone activity and the development of tolerance to morphine analgesia during pain. Our hypothesis predicts that a strain of rat identified to lack typical stress-induced endocrine responses (Lewis strain) will not show an increase in corticosterone following pain, and thus will not show a blockade of tolerance by pain. This proposal will also evaluate the biobehavioral factors that influence the development of tolerance during pain by examining the contribution of type of pain, corticosterone, and method of morphine administration. We will examine the conditions in which pain attenuates tolerance versus conditions in which pain fails to attenuate tolerance. Our hypothesis predicts that the effects of pain and corticosterone on tolerance development can be predicted based on the presence or absence of environmental cues associated with morphine administration. The identification of the biological and behavioral factors that influence tolerance to morphine analgesia during pain will provide insights into the mechanisms that determine the development of aped tolerance in the clinical setting.