Mechanisms of Carisoprodol Abuse

描述（由申请人提供）：Carisoprodol （Soma(R)）是一种中枢作用的骨骼肌松弛剂，经常用于治疗急性肌肉骨骼疾病。近年来，人们越来越担心卡异丙醇可能被滥用。1991年，carisoprodol在234种可能被滥用的药物中排名第54位。仅仅八年后，药物滥用警告网络就将卡异丙醇列为第14大滥用药物，排名高于羟可酮、美沙酮和LSD。为了支持这一点，最近的报告证实了滥用carisoprodol的危险，包括严重戒断导致癫痫发作和死亡。然而，其作用机制尚不清楚。直到最近，人们普遍认为卡异丙醇的镇静作用主要是由于其代谢物甲基丙酸酯。然而，在我们实验室进行的初步体内和体外研究表明，carisoprodol本身是活跃的，其作用似乎是通过GABAA受体（GABAAR）的新调节介导的，GABAA受体是哺乳动物大脑中主要的抑制性神经递质受体。这可能是carisoprodol增强中枢神经系统抑制剂镇静作用的基础，有助于其滥用的可能性。事实上，由于对卡异丙酚滥用情况增加的关切，禁毒执法机构已与国家药物滥用研究所联系，请求协助确定卡异丙酚的滥用责任。基于我们的初步发现，我们假设carisoprodol本身会引起抑郁性中枢神经系统效应，并且这些作用是通过与GABAA受体的一种新的相互作用来介导的。拟议研究的总体目标是在行为和分子水平上确定介导卡异丙醇滥用的机制。我们将利用体内（药物鉴别和中毒观察，耐受性和戒断，以及药代动力学分析）和体外（评估卡异丙醇对重组GABAA受体的特定构型）方法来解决以下具体目标：1)表征卡异丙醇的鉴别刺激效应；2)研究carisoprodol在体内是自身产生作用还是需要代谢成meprobate；3)评价卡异丙醇的依赖程度和戒断程度；4)鉴定GABAA受体亚基对异丙醇的变构调节和直接门控作用至关重要；5)鉴定GABAA受体亚基结构域对异丙醇的敏感性。鉴于卡异丙醇滥用目前和潜在的危险，确定该药物的作用机制至关重要。我们提出的研究将大大增加我们对卡异丙醇作为治疗药物和滥用药物的作用机制的理解。这一知识可能为治疗卡异丙醇依赖和戒断提供见解。公共卫生相关性：肌肉松弛剂Carisoprodol （Soma(R)）正以惊人的速度日益被滥用；停止过度使用这种药物会引起癫痫发作甚至死亡。迫切需要开发能够治疗这些症状的新药，以及不太可能被滥用的新药。拟议的研究将提供解决这两项目前未得到满足的医疗需求所需的基本信息。

DESCRIPTION (provided by applicant): Carisoprodol (Soma(R)) is a centrally-acting skeletal muscle relaxant frequently prescribed for the treatment of acute musculoskeletal conditions. In recent years, there has been increasing concern regarding carisoprodol's potential as a drug of abuse. In 1991, carisoprodol was ranked 54th among 234 drugs with abuse potential. Only eight years later, the Drug Abuse Warning Network identified carisoprodol as the 14th most abused drug, ranking higher than oxycodone, methadone, and LSD. In support of this, recent reports have substantiated the dangers involved in carisoprodol abuse, including severe withdrawal leading to seizures and death. However, its mechanism of action remains unclear. Until recently, it was widely accepted that the sedative effects of carisoprodol were predominantly due to its metabolite, meprobamate. However, preliminary in vivo and in vitro studies conducted in our laboratory demonstrate that carisoprodol itself is active, and its actions appear to be mediated via novel modulation of the GABAA receptor (GABAAR), the predominant inhibitory neurotransmitter receptor in mammalian brain. This may underlie the capacity of carisoprodol to enhance the sedative effects of CNS depressants, contributing to its potential for abuse. Indeed, concerns about the rise in abuse of carisoprodol have led the Drug Enforcement Agency to contact the National Institute on Drug Abuse for assistance in determining the abuse liability of carisoprodol. Based on our preliminary findings, we hypothesize that carisoprodol itself causes depressive CNS effects, and that these actions are mediated via a novel interaction with the GABAA receptor. The overall goal of the proposed study is to identify the mechanisms that mediate carisoprodol abuse, at both the behavioral and molecular level. We will utilize both in vivo (drug discrimination and observation of intoxication, tolerance and withdrawal, and pharmacokinetic analysis) and in vitro (assessment of carisoprodol on specific configurations of recombinant GABAA receptors) approaches to address the following specific aims: 1) To characterize the discriminative stimulus effects of carisoprodol; 2) To investigate whether carisoprodol produces effects on its own in vivo or requires being metabolized to meprobamate; 3) To assess the extent of carisoprodol dependence and severity of withdrawal; 4) To identify GABAA receptor subunits critical for allosteric modulatory and direct gating effects of carisoprodol; and 5) To identify GABAA receptor subunit domains that confer carisoprodol sensitivity. Given the present and potential dangers posed by carisoprodol abuse, it is of crucial importance to determine the mechanism of action of this drug. Our proposed studies will substantially increase our understanding of the mechanism of action of carisoprodol as a therapeutic agent and as a drug of abuse. This knowledge may provide insight into treating carisoprodol dependence, and withdrawal. PUBLIC HEALTH RELEVANCE: The muscle relaxant Carisoprodol (Soma(R)) is being abused increasingly at an alarming rate; withdrawal from overuse of this drug can cause seizures and even death. There is an urgent need to develop new drugs that can treat these symptoms, as well as new drugs that are less likely to be abused. The proposed studies will provide the fundamental information needed to address both of these current unmet medical needs.