Persistent morphine memory during abstinence in female, but not male, metabotropic glutamate 5 receptor knockout mice.

Opioid use disorder is a chronic, relapsing condition, and men and women differ in their susceptibility to opioid reward and relapse risk. With limited treatment options for opioid use disorder, the metabotropic glutamate 5 receptor (mGlu5) presents a promising new therapeutic target. mGlu5 is highly expressed in brain regions associated with drug-related behaviour and has been implicated in opioid reward through pharmacological studies; however, the sex-specific nature of this relationship is unclear. Here, we examined morphine-induced conditioned place preference (CPP) and locomotor activity in adult male and female mGlu5 knockout (KO) and wild type-like (WT) mice. We found dose- and sex-dependent effects of mGlu5 deletion on morphine reward memory and locomotion. Female mGlu5 KO mice exhibited persistent memory for 5 mg/kg morphine, lasting up to five weeks, which was not observed in female WT mice. In contrast, male WT mice showed persistent memory for 10 mg/kg morphine, which was not evident in male mGlu5 KO mice; this dose was not rewarding in female mice of either genotype. Furthermore, 5 mg/kg morphine decreased locomotion in mGlu5 KO mice but increased locomotion in WT mice, whereas 10 mg/kg morphine increased locomotion in both genotypes. This pattern was observed in both sexes. Overall, we discovered a sex-specific role for mGlu5 in modulating the rewarding and locomotor response to morphine. The results underscore the importance of including both sexes in preclinical models of opioid use disorder and suggest mGlu5 as a potential therapeutic target for addressing relapse risk, particularly in women.