Sex dependence of opioid-mediated responses to subanesthetic ketamine

Ketamine rapidly reduces depressive symptoms in treatment-resistant depression, but its mechanisms are not fully understood. Recent clinical evidence controversially suggests that ketamine's efficacy may depend on opioid signaling. In rats, blocking opioid receptors suppressed ketamine-induced neurophysiologic changes in brain regions linked to depression and reward, but did not affect changes from a more selective NMDA receptor antagonist. This opioid-dependent response was strongly sex-dependent: absent in females and reversed by removing male gonads. Similar sex-dependent opioid effects appeared in ketamine-evoked structural plasticity and behavioral sensitization. These results indicate that ketamine may induce affective responses via opioid signaling, with subject sex as a strong influence, warranting direct assessment in future clinical trials.

Study at a glance

Abstract

Subanesthetic ketamine rapidly and robustly reduces depressive symptoms in patients with treatment-resistant depression. While it is commonly classified as an N-methyl D-aspartate receptor (NMDAR) antagonist, our picture of ketamine’s mechanistic underpinnings is incomplete. Recent clinical evidence has indicated, controversially, that a component of the efficacy of ketamine in depression may be opioid dependent. Using pharmacological functional ultrasound imaging in rats, we found that blocking opioid receptors suppressed neurophysiologic changes evoked by ketamine, but not by a more selective NMDAR antagonist, in regions implicated in the pathophysiology of depression and in reward processing. Importantly, this opioid-dependent response was strongly sex dependent, as it was not evident in female subjects and was fully reversed by surgical removal of the male gonads. We observed similar opioid-mediated sex-dependent effects in ketamine-evoked structural plasticity and behavioral sensitization. Together, these results underscore the potential for ketamine to induce its affective responses via opioid signaling, and indicate that this opioid dependence may be strongly influenced by subject sex. These factors should be more directly assessed in future clinical trials.