Mu Opioid Receptor Activation Is Required for NMDA Receptor Antagonist Effects on Stress-Induced Maladaptive Behavior

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.