Pharmacological and behavioral effects of MCAM: a long-acting, μ opioid receptor antagonist for treatment of opioid overdose and opioid abuse disorder

美罗华(MCAM)是一种长效的阿片受体拮抗剂，在 阿片类药物过量和阿片滥用障碍的治疗。我们建议使用体外和体外方法评估MCAM 体内测量，比较MCAM与阿片类拮抗剂纳曲酮和纳洛酮的作用， 目前分别用于治疗滥用和过量用药。我们假设， 药理学特性，包括结合动力学和阿片类药物滥用无法克服的，将 将MCAM与其他阿片受体拮抗剂区分开来。在体外，我们将MCAM与 纳洛酮的结合/解离动力学，阿片类激动剂(芬太尼，吗啡)的可控性， 拮抗持续时间(MCAM不可逆？)，并测定MCAM的药理特性 多条细胞信号通路。将在大鼠身上采取活体措施，以确定作用持续时间和 MCAM在几种相关准备中的不可逾越。μ阿片受体激动剂吗啡的逆转作用 和芬太尼)引起的呼吸抑制将使用全身体积描记进行评估。相对的 在该制剂中也将测量MCAM与纳洛酮提供的过量保护的持续时间。 预防阿片滥用的模型将利用μ阿片受体增强效应的措施 激动剂瑞芬太尼。MCAM与纳曲酮的相对不可克服性和作用持续时间(目前 用于治疗滥用)在阻断瑞芬太尼的强化作用中将在该制剂中确立。这个 每日有效的最小剂量的MCAM预防瑞芬太尼的强化作用 提供在MCAM缓释制剂中适用的递送速率的信息。 还将比较MCAM和纳洛酮诱导阿片类药物戒断的相对能力。 依赖的老鼠。最后，因为目前的阿片类止痛药如果是长效拮抗剂就不会有效 (例如，MCAM)用于治疗滥用和/或过量用药，我们将评估外周限制的可行性 Kappa阿片受体激动剂在MCAM存在时用作止痛剂。激活 在外周痛觉神经元上表达的外周kappa阿片受体可以产生水平的 止痛效果相当于局部麻醉剂，因此可能是一种很好的治疗方法 长期阻断阿片受体功能的个体疼痛的治疗。共同努力，这项工作将 提供有关MCAM是否比纳洛酮和纳曲酮具有实质性优势的所需信息 阻止或防止阿片类药物滥用的行为。

Methocinnamox (MCAM) is a long-acting µ-opioid receptor antagonist that may have distinct advantages in the treatment of both opioid overdose and opioid abuse disorder. We propose to evaluate MCAM using in vitro and in vivo measures, comparing the actions of MCAM with those of the opioid antagonists naltrexone and naloxone, that are currently used to treat abuse and overdose, respectively. We hypothesize that differences in pharmacological properties, including binding kinetics and non-surmountablility by opioids of abuse, will distinguish MCAM from those of the other opioid receptor antagonists. In vitro, we will compare MCAM to naloxone for kinetics of association/dissociation, surmountability by opioid agonists (fentanyl, morphine), the duration of antagonism (is MCAM irreversible?), and determine the pharmacological characteristics of MCAM at multiple cellular signaling pathways. In vivo measures will be taken in rats to ascertain the duration of action and insurmountability of MCAM in several relevant preparations. Reversal of μ opioid receptor agonist- (morphine and fentanyl) induced respiratory depression will be evaluated using whole body plethysmography. The relative duration of overdose protection afforded by MCAM versus naloxone will be measured in this preparation as well. Models of protection against opioid abuse will utilize measures of the reinforcing effects of the μ opioid receptor agonist remifentanil. The relative insurmountability and duration of action of MCAM versus naltrexone (currently used to treat abuse) in blocking the reinforcing effects of remifentanil will be established in this preparation. The smallest dose of MCAM that is effective when given daily in preventing the reinforcing effects of remifentanil will provide information on the rate of delivery that would be appropriate in a sustained-release formulation of MCAM. Comparisons will also be made of the relative ability of MCAM versus naloxone to elicit withdrawal in opioid- dependent rats. Lastly, because current µ opioid analgesic drugs will not be effective if a long-acting antagonist (e.g., MCAM) is used to treat abuse and/or overdose, we will assess the feasibility of peripherally-restricted administration of kappa opioid receptor agonists for use as analgesic agents in the presence of MCAM. Activation of peripheral kappa opioid receptors that are expressed on peripheral pain-sensing neurons can produce a level of analgesia equivalent to that produced by a local anesthetic and therefore may be a good approach for the treatment of pain in individuals with long-term blockade of µ opioid receptor function. Together, this work will provide needed information about whether MCAM offers substantial advantage over naloxone and naltrexone in blocking or preventing the actions of opioid drugs of abuse.