Neuropharmacology of neuropathic pain and addiction

描述（由申请人提供）： 申请的研究提案部分将评估外源性和内源性胍丁胺在阿片类药物介导的事件中的作用。胍丁胺在哺乳动物中枢神经系统中被发现具有拮抗NMDA受体和抑制一氧化氮合酶（NOS）的作用。外源性给予胍丁胺也显示出抑制NMDA受体/NOS依赖性行为，包括慢性疼痛、阿片耐受和自我给药。这些先前的研究在给药途径、剂量反应或药效学评价方面受到很大限制。为了确定胍丁胺有效预防阿片类事件的治疗窗，将在脊髓阿片类镇痛剂耐受模型以及阿片类自我给药模型中的不同时间点中枢和全身给予外源性胍丁胺。定义外源性胍丁胺在阿片样物质相关行为中的药效学特征将促进我们对这种分子的治疗效用和内源性作用的理解。阐明内源性胍丁胺在阿片类镇痛耐受和药物滥用中的作用可能会导致新的治疗靶点的确定。

DESCRIPTION (provided by applicant): The research proposal component of the application will evaluate the effects of both exogenous and endogenous agmatine in opioid-mediated events. Agmatine has been detected in mammalian central nervous system and found to antagonize NMDA receptors and inhibit nitric oxide synthase (NOS). Exogenously administered agmatine has also been shown to inhibit NMDA receptor/NOS-dependent behavior including chronic pain, and opioid tolerance and self-administration. These previous studies have been largely limited in terms of route of administration, dose-response, or pharmacodynamic evaluation. To determine the therapeutic window in which agmatine is effective for prevention of opioidergic events, exogenous agmatine will be administered centrally and systemically at varying time points in a model of spinal opioid analgesic tolerance as well as a model of opioid self-administration. Definition of the pharmacodynamic profile of exogenous agmatine in opioid-related behavior will advance our understanding of the therapeutic utility and endogenous role of this molecule. Elucidation of the role of the endogenous agmatine in opioid analgesic tolerance and drug abuse may lead to the identification of new therapeutic targets.