Delta Opioid Receptor (DOR) Agonist Activity of Buprenorphine in Mice

Abstract

Buprenorphine is an approved method of treatment for opioid use disorder (OUD), and it is under investigation for cocaine use disorder-- for which there are no FDA-approved, pharmacological treatments. Buprenorphine is considered a mixed efficacy opioid ligand, and its partial agonist activity at the mu opioid receptor (MOR) is thought to mediate the therapeutic effects for OUD. There is also evidence that it acts as a kappa opioid receptor (KOR) and delta opioid receptor (DOR) antagonist and a nociception/orphanin FQ receptor (NOPR) agonist. However, one recent report found buprenorphine to act as a partial DOR agonist in cells expressing human opioid receptors (Bidlack et al., 2018). The goal of the present study was to investigate the in vivo activity of buprenorphine at DOR in rodents. Male C57BL6/N mice were used to evaluate the effects of buprenorphine on pentylenetetrazol (PTZ)-induced convulsive activity and in the mouse forced swim test. Buprenorphine did not produce overt convulsions in mice but dose-dependently increased PTZ-induced convulsions with 32 mg/kg buprenorphine as the maximally effective dose, and these effects were attenuated by the DOR antagonist naltrindole. Also, buprenorphine (0.01-0.1 mg/kg) decreased immobility in the mouse forced swim test, which was blocked by pretreatment with naltrindole. Together, these data demonstrate that buprenorphine produces DOR-mediated antidepressant-like effects and potentiates PTZ-induced convulsions, suggesting that buprenorphine acts as a partial DOR agonist in mice. Interestingly, there is a large separation between doses that produce potential antidepressant-like effects and pro-convulsive effects. Future studies will investigate whether this large separation between DOR-mediated effects are due to the complex pharmacology of buprenorphine. Further, these data offer additional insight into the activity of buprenorphine, which could help elucidate the mechanism needed for successful treatment of opioid or cocaine use disorder. These studies were supported in part by R21 DA041565 and DA007315.