Effects of naltrexone on gabapentin reward and buprenorphine combinations in male mice

Gabapentin (GBP), an anticonvulsant approved for seizures and neuropathic pain, is frequently co-prescribed with buprenorphine (BUP), a partial mu-opioid receptor (MOR) agonist, to manage withdrawal and pain in individuals with opioid use disorder (OUD). While GBP is generally considered safe, emerging evidence suggests abuse potential when combined with opioids. This study used the conditioned place preference (CPP) paradigm to assess the rewarding effects of GBP alone and in combination with BUP. Male mice underwent standard CPP procedures. Treatment groups included GBP (100 or 300 mg/kg) alone or combined with BUP (1.0 mg/kg). Naltrexone (NAL; 10.0 mg/kg), an opioid receptor antagonist, was co-administered with each treatment to assess MOR involvement. Drugs and saline were alternated over eight consecutive days. GBP induced significant CPP at both doses, but only the 100 mg/kg effect was prevented by NAL. BUP-induced CPP was prevented by NAL. Co-administration of GBP and BUP at either dose produced a CPP, which persisted despite NAL treatment. Both opioid and non-opioid systems may contribute to the rewarding effects of GBP and GBP-BUP combinations. These findings raise important concerns about the abuse potential of GBP, particularly when co-prescribed with BUP, and underscore the need for cautious clinical use and further investigation into non-opioid mechanisms of reward.