THE OFQ/N/ORL-1 RECEPTOR SYSTEM & COCAINE SENSITIZATION

OFQ/N/ORL-1 受体系统

基本信息

批准号：
7089864
负责人：
KABIRULLAH LUTFY
金额：
$ 16.84万
依托单位：
WESTERN UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-15 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7089864
关键词：
behavioral /social science research tag behavioral habituation /sensitization brain morphology cocaine craving disease /disorder model drug addiction endogenous opioid gene targeting genetically modified animals laboratory mouse opioid receptor radioimmunoassay receptor expression tegmentum

项目摘要

DESCRIPTION (provided by applicant): Chronic use of cocaine in humans results in long-lasting alterations in brain structure and function. In laboratory animals, repeated intermittent cocaine administration produces an augmented behavioral response to a subsequent challenge dose of the drug. This phenomenon, referred to as behavioral sensitization, may be important in cocaine craving, a central factor in many cases of drug relapse. The endogenous opioid peptide/receptor system has been implicated in cocaine sensitization. However, the role of the OFQ/N/ORL-1 receptor system has not been characterized in this phenomenon. Our preliminary data show that concomitant OFQ/N administration with cocaine blocks the development of cocaine sensitization and this action of OFQ/N is antagonized by J-113397, an ORL-1 receptor antagonist. Thus, the OFQ/N/ORL-1 receptor system plays an important role in blocking this phenomenon and may be a potential target to develop drugs with anti-craving activity. In order to characterize the neurobiological substrate for such an action of OFQ/N, we will elucidate the site of action of OFQ/N. Additionally, since OFQ/N or related drugs will be used to treat cocaine addicts, using sensitization as an animal model of drug craving, we will determine if OFQ/N could reverse an already existing sensitized response, a more clinically relevant issue. Our preliminary data also show that the level of hypothalamic OFQ/N increases after repeated cocaine treatment, indicating that the endogenous OFQ/N/ORL-1 receptor system may be altered during development of sensitization. Thus, using RIA and binding assays, we will measure levels of OFQ/N and its receptor after cocaine treatment in brain regions involved in cocaine craving. Using knockout mice, we will also study the development of sensitization in the absence of the ORL-1 receptor or OFQ/N. The studies proposed in this grant will elucidate the role of OFQ/N/ORL-1 receptor system in cocaine sensitization and possibly provide important and useful information toward developing possible treatments for cocaine addiction.

描述（由申请人提供）：人类长期使用可卡因会导致大脑结构和功能的长期改变。在实验动物中，重复间歇性给予可卡因会产生对后续挑战剂量药物的增强行为反应。这种现象被称为行为敏化，可能在可卡因渴望中发挥重要作用，而可卡因渴望是许多吸毒复发病例的核心因素。内源性阿片肽/受体系统与可卡因致敏有关。然而，OFQ/N/ORL-1受体系统在这种现象中的作用尚未得到表征。我们的初步数据表明，OFQ/N 与可卡因同时给药可阻断可卡因致敏的发生，并且 OFQ/N 的这种作用被 ORL-1 受体拮抗剂 J-113397 拮抗。因此，OFQ/N/ORL-1受体系统在阻断这种现象中发挥着重要作用，并且可能是开发具有抗渴求活性的药物的潜在靶点。为了表征 OFQ/N 这种作用的神经生物学底物，我们将阐明 OFQ/N 的作用位点。此外，由于 OFQ/N 或相关药物将用于治疗可卡因成瘾者，使用致敏作用作为药物渴望的动物模型，我们将确定 OFQ/N 是否可以逆转已经存在的致敏反应，这是一个与临床更相关的问题。我们的初步数据还表明，重复可卡因治疗后下丘脑 OFQ/N 水平升高，表明内源性 OFQ/N/ORL-1 受体系统可能在致敏过程中发生改变。因此，使用 RIA 和结合测定，我们将测量可卡因治疗后涉及可卡因渴望的大脑区域中 OFQ/N 及其受体的水平。我们还将使用基因敲除小鼠来研究在缺少 ORL-1 受体或 OFQ/N 的情况下致敏的发展。这笔资助中提出的研究将阐明 OFQ/N/ORL-1 受体系统在可卡因致敏中的作用，并可能为开发可卡因成瘾的可能治疗方法提供重要且有用的信息。