OFQ MODULATION OF OPIATE TOLERANCE DEPENDENCE AND REWARD

适应长期阿片类药物暴露会给成瘾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成本。 尽管多年的深入研究旨在了解阿片类药物的耐受性和依赖性，这些变化的机制仍然不清楚。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，并且OFQ也被发现与阿片家族的成员在结构上相关。 也许令人惊讶的是，考虑到这些和其他相似之处（例如，与腺苷酸环化酶的负偶联和重叠的中枢神经系统分布），OFQ作用于其受体，似乎起内源性抗阿片样物质的作用。最近的证据表明，这种肽的活性变化可能是与长期暴露于阿片类药物引起的神经适应相关的过程的基础。 最值得注意的是，OFQ给药阻断阿片类药物介导的应激诱导的镇痛和吗啡镇痛，并且在重复吗啡给药后OFQ肽及其受体都上调。 此外，缺乏OFQ-R的转基因小鼠中阿片耐受性的发展减少（上田等人，1997年）。 以下研究拟探讨孤啡肽对长期暴露于阿片类药物引起的变化的影响。 由于共同管理OFQ与吗啡将阻断吗啡的作用，而不影响吗啡受体占用，我们建议测试是否共同管理将改变吗啡耐受，戒断和位置偏爱的发展。 这些研究的信息将有助于确定吗啡与受体的相互作用是否足以产生此类变化，从而有助于回答长期暴露于阿片类药物后的神经适应是否由细胞或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药物成瘾者和疼痛患者开发新型治疗策略和药物疗法。

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.