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OFQ MODULATION OF OPIATE TOLERANCE DEPENDENCE AND REWARD

OFQ 对阿片类药物耐受性依赖性和奖励的调节

基本信息

批准号：
6175549
负责人：
JUDITH E GRISEL
金额：
$ 6.61万
依托单位：
FURMAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-25 至 2002-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6175549
关键词：
analgesia drug addiction antagonist drug tolerance drug withdrawal endogenous opioid laboratory mouse ligands morphine naloxone narcotic antagonists operant conditionings opioid receptor pain

项目摘要

Adaption to chronic opiate exposure leads to tremendous health and social problems for addicts and pain patients, and thus imposes great costs for society in general. Despite years of intensive research directed toward understanding opiate tolerance and dependence, mechanisms of these changes remain unclear. Orphanin FQ is the recently identified endogenous ligand for the orphan opioid receptor (OFQ-R). OFQ-R was discovered by virtue of its high sequence homology to the family of opiate receptors, and OFQ also was found to be structurally related to members of the opioid family. Perhaps surprisingly, given these and other similarities (e.g., negative coupling to adenylate cyclase and overlapping central nervous system distribution), OFQ, acting at its receptor, appears to function as an endogenous antiopioid. Recent evidence suggests that changes in activity of this peptide may underlie processes associated with the neuroadaptation that ensues from chronic exposure to opiates. Most notably, OFQ administration blocks both opioid-mediated stress-induced analgesia and morphine analgesia, and there is an upregulation in both OFQ peptide and its receptor following repeated morphine administration. Furthermore, the development of opiate tolerance is reduced in transgenic mice that lack the OFQ-R (Ueda et al., 1997). The following studies are proposed to investigate the effect of OFQ on changes resulting from chronic exposure to opiates. Because coadministration of OFQ with morphine will block morphine effects without affecting morphine receptor occupancy, we propose to test whether such coadministration will alter the development of morphine tolerance, withdrawal, and place preference. Information from these studies will help determine whether morphine-receptor interactions are sufficient for such changes and thus help to answer the question of whether neuroadaption following chronic exposure to opiates results from cellular or systemic phenomena. Clinical applications of this work might include the development of novel treatment strategies and pharmacotherapies for opiate addicts and pain sufferers.

适应长期的阿片类药物暴露会给吸毒者和疼痛患者带来巨大的健康和社会问题，从而给整个社会带来巨大的代价。尽管多年的密集研究旨在了解阿片类药物的耐受性和依赖性，但这些变化的机制仍不清楚。孤儿素FQ是最近发现的孤儿阿片受体(OFQ-R)的内源性配体。OFQ-R是由于其与阿片受体家族的高度序列同源性而被发现的，而且OFQ也被发现在结构上与阿片受体家族的成员有关。也许令人惊讶的是，考虑到这些和其他相似之处(例如，与腺苷环化酶负耦合和重叠的中枢神经系统分布)，OFQ作用于其受体，似乎起到内源性阿片类药物的作用。最近的证据表明，这种多肽活性的变化可能是与长期接触阿片类药物导致的神经适应相关的过程的基础。最值得注意的是，OFQ既阻断了阿片介导的应激镇痛，也阻断了吗啡的镇痛作用，重复给药后，OFQ多肽及其受体均上调。此外，在缺乏OFQ-R的转基因小鼠中，阿片类药物耐受性的发展会减少(Ueda等人，1997年)。建议进行以下研究，以调查OFQ对长期接触阿片类药物引起的变化的影响。因为孤啡肽和吗啡联合给药可以阻断吗啡的作用而不影响吗啡受体的占有率，所以我们建议测试这种联合给药是否会改变吗啡耐受、戒断和位置偏爱的发展。来自这些研究的信息将有助于确定吗啡-受体相互作用是否足以引起这种变化，从而有助于回答长期接触阿片类药物后的神经适应是由细胞现象还是全身现象引起的问题。这项工作的临床应用可能包括为阿片类成瘾者和疼痛患者开发新的治疗策略和药物疗法。