Neuropharmacology of neuropathic pain and addiction

描述(由申请人提供)： 申请的研究建议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效果。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。外源性给药的胍丁胺也被证明可以抑制NMDA受体/NOS依赖的行为，包括慢性疼痛、阿片耐受和自我给药。这些先前的研究主要局限于给药途径、剂量反应或药效学评价。为了确定胍丁胺预防阿片能事件的有效治疗窗口，在脊髓阿片类止痛耐受模型和阿片类药物自身给药模型中，外源性胍丁胺将在不同的时间点集中和系统地给予。明确外源性胍丁胺在阿片类药物相关行为中的药效学特征将促进我们对该分子的治疗作用和内源性作用的理解。阐明内源性胍丁胺在阿片类止痛耐受和药物滥用中的作用可能有助于发现新的治疗靶点。

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.