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

Methocinnamox（MCAM）是一种长效μ-阿片受体拮抗剂，可能在以下方面具有明显优势： 治疗阿片类药物过量和阿片类药物滥用障碍。我们建议使用体外和 体内测量，比较MCAM与阿片类拮抗剂纳洛酮和纳洛酮的作用， 目前分别用于治疗药物滥用和药物过量。我们假设， 药理学性质，包括结合动力学和滥用阿片类药物的不可克服性， 将MCAM与其他阿片受体拮抗剂区分开来。在体外，我们将MCAM与 纳洛酮结合/解离动力学，阿片类激动剂（芬太尼，吗啡）的可克服性， 拮抗作用持续时间（MCAM是否不可逆？），并确定MCAM的药理学特征， 多种细胞信号通路。将在大鼠中进行体内测量以确定作用持续时间， MCAM在几种相关制剂中的不可克服性。μ阿片受体激动剂吗啡的抑制作用 和芬太尼）诱导的呼吸抑制将使用全身体积描记法进行评价。的相对 还将在该制剂中测量MCAM相对于纳洛酮提供的过量保护的持续时间。 针对阿片类药物滥用的保护模型将利用μ阿片受体的增强作用的措施 激动剂瑞芬太尼。MCAM相对于纳洛酮（目前 用于治疗滥用）在阻断瑞芬太尼的增强作用中的作用。的 每天给予最小剂量的MCAM有效防止瑞芬太尼的强化作用， 提供适当的MCAM缓释制剂的递送速率信息。 还将比较MCAM与纳洛酮引起阿片类药物戒断的相对能力- 依赖的老鼠最后，由于目前的μ阿片类镇痛药物将不会有效，如果长效拮抗剂 (e.g., MCAM）用于治疗滥用和/或过量，我们将评估外周限制性 在MCAM的存在下施用κ阿片样物质受体激动剂用作镇痛剂。激活 在外周痛觉神经元上表达的外周κ阿片受体的水平 镇痛相当于由局部麻醉剂产生的，因此可能是一个很好的方法， 治疗长期阻断μ阿片受体功能的个体疼痛。这项工作将 提供关于MCAM是否在以下方面比纳洛酮和纳洛酮具有实质性优势的所需信息： 阻断或防止阿片类药物滥用的作用。

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.