Methocinnamox(UT Health San Antonio)

Naloxone and nalmefene are μ opioid receptor (MOR) antagonist medications for reversing opioid overdose and naltrexone is a MOR antagonist medication for treating opioid use disorder (preventing relapse). MOR agonist medications for treating opioid use disorder include methadone and buprenorphine. The magnitude of effect of buprenorphine can be less than the effect of higher efficacy MOR agonists with some effects of buprenorphine (eg, ventilatory depression) resistant to reversal by naloxone, compared with reversal of the effects of other MOR agonists. Drug discrimination was used to compare the ability of naloxone, naltrexone, nalmefene, and methocinnamox (MCAM) to prevent and reverse the effects of buprenorphine and the ultrapotent fentanyl analog carfentanil in male and female rats discriminating fentanyl from saline. Naloxone, naltrexone, nalmefene, and MCAM (0.01-0.1 mg/kg) were equipotent at preventing the discriminative stimulus effects of 0.01 mg/kg buprenorphine and 0.0001 mg/kg carfentanil. Compared with their potencies to prevent discriminative stimulus effects, naloxone, naltrexone, and nalmefene were ≥92-fold less potent in reversing the discriminative stimulus effects of buprenorphine and ≥31-fold less potent in reversing the discriminative stimulus effects of carfentanil. In contrast, MCAM was equipotent in preventing and reversing the discriminative stimulus effects of buprenorphine and carfentanil. There was no significant difference in the onset of action of naloxone, naltrexone, nalmefene, or MCAM. The greater potency of MCAM, compared with naloxone, naltrexone, and nalmefene for reversing the effects of buprenorphine and carfentanil might translate to MCAM reversing adverse effects of a wide range of MOR agonists in patients. SIGNIFICANCE STATEMENT: Buprenorphine, a μ opioid receptor (MOR) agonist used to treat opioid use disorder, can produce adverse effects that are reportedly more difficult to reverse with naloxone, compared with reversal of the effects of other MOR agonists. This study provides evidence for the potential utility of the MOR antagonist methocinnamox to reverse the adverse effects of buprenorphine by demonstrating the relatively greater potency of methocinnamox, compared with currently available MOR antagonists, to reverse the discriminative stimulus effects of buprenorphine and carfentanil.

Contradictory evidence has emerged regarding the role of the mu opioid receptor (MOR) in the antidepressant actions of (R,S)-ketamine.

Here, we used the long-acting MOR-selective antagonist methocinnamox (MCAM) to determine the contribution of MOR to the actions of (R,S)-ketamine and the more selective NMDA receptor (NMDAR) antagonist fluoroethylnormemantine (FENM) against stress-induced maladaptive behaviors. (R,S)-ketamine enantiomers and metabolites and FENM were assessed for their ability to directly activate MOR in cell signaling assays. (R,S)-ketamine and FENM were tested in various behavioral paradigms with vehicle or MCAM pretreatment. Patch clamp electrophysiology was used to determine the effects of MOR antagonism on ventral hippocampal CA3 glutamatergic activity after (R,S)-ketamine administration.

(R,S)-ketamine and its enantiomers showed weak partial agonism of MOR, whereas the potency and efficacy of FENM were negligible. The antinociceptive effect of (R,S)-ketamine was both more potent and more sensitive to blockade by MCAM than that of FENM. When given either before or after stress, both (R,S)-ketamine and FENM reduced behavioral despair. MCAM prevented the effects of both NMDAR antagonists given before or after stress, despite their differences in direct MOR activity and antinociception.

MOR activation is required for the efficacy of both (R,S)-ketamine and FENM against stress-induced maladaptive behavior, suggesting that these compounds function through an indirect effect of NMDAR antagonism on endogenous opioid signaling.