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.