Morphine/Cannabinoid Interactions: Antinociception, Tolerance, and Sensitization

吗啡/大麻素相互作用：镇痛、耐受和致敏

基本信息

批准号：
7673144
负责人：
Laurence L. Miller
金额：
$ 2.98万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2011-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Agonists of the mu-opioid receptor, such as morphine, are some of the most effective and widely used drugs in the treatment of pain. However, these compounds also have significant effects that limit their therapeutic potential such as the development of tolerance and dependence. One area of interest that has arisen in the search for ways to reduce these unwanted effects involves combining the administration of opioid compounds with drugs that act directly on different systems, but also interact with the opioid system. Ideally, such combinations would enhance the antinociceptive effects of the opioid without increasing unwanted effects. The cannabinoid system interacts with the opioid system and manipulations of cannabinoid signaling may have the potential to be used in this manner. Indeed, cannabinoid agonists have been shown to enhance the antinociceptive effects of opioids such as morphine. However, there is evidence that suggests that cannabinoid/opioid agonist combinations may also produce unwanted effects. For instance, cannabinoid agonists have been shown to enhance the effects of opioids that are associated with their abuse potential. Direct activation of the receptor is not the only way to alter the activity of the cannabinoid system. Recent evidence suggests that altering cannabinoid signaling by manipulating the metabolism and uptake of endogenous cannabinoids, such as anandamide, may hold a therapeutic potential. For intance, altering cannabinoid signaling in this manner produces antinociception, but does not produces some of the unwanted effects associatedwith the administration of cannabinoid agonists. The experiments proposed here build upon these observations by determining whether compounds that inhibit the transport or metabolism of endocannabinoids can enhance the acute antinociceptive effects of morphine (Specific Aim I), and alter the development of tolerance to morphine's antinociceptive effects (Specific Aim II). The experiments described in this proposal will extend existing knowledge regarding the role of the cannabinoid system as a therapeutic target in the treatment of pain. The proposal is also comprised of investigations that are designed to address questions related to the abuse potential of drugs. Findings from these experiments may provide insights that translate to clinical applications.

描述（由申请人提供）：mu-阿片受体激动剂，例如吗啡，是治疗疼痛中最有效和最广泛使用的药物之一。然而，这些化合物也具有限制其治疗潜力的显着作用，例如产生耐受性和依赖性。在寻找减少这些不良影响的方法中出现的一个令人感兴趣的领域涉及将阿片类化合物的施用与直接作用于不同系统但也与阿片类系统相互作用的药物相结合。理想情况下，此类组合将增强阿片类药物的抗伤害作用，而不增加不良作用。大麻素系统与阿片类系统相互作用，大麻素信号传导的操纵可能有潜力以这种方式使用。事实上，大麻素激动剂已被证明可以增强吗啡等阿片类药物的镇痛作用。然而，有证据表明大麻素/阿片类激动剂组合也可能产生不良影响。例如，大麻素激动剂已被证明可以增强阿片类药物的作用，而这与其滥用潜力有关。直接激活受体并不是改变大麻素系统活性的唯一方法。最近的证据表明，通过操纵内源性大麻素（例如 anandamide）的代谢和摄取来改变大麻素信号传导可能具有治疗潜力。例如，以这种方式改变大麻素信号传导会产生镇痛作用，但不会产生与施用大麻素激动剂相关的一些不良作用。本文提出的实验基于这些观察结果，通过确定抑制内源性大麻素转运或代谢的化合物是否可以增强吗啡的急性镇痛作用（具体目标 I），并改变对吗啡镇痛作用的耐受性的发展（具体目标 II）。该提案中描述的实验将扩展有关大麻素系统作为疼痛治疗目标的作用的现有知识。该提案还包括旨在解决与药物滥用潜力相关的问题的调查。这些实验的结果可能会提供转化为临床应用的见解。