Sex differences in the response of mice to opioid antagonists

Abstract

Kappa opioid receptors (KOP) in the central nervous system have been established to be significant regulators of a variety of mental diseases, including anxiety and depression. Accordingly, KOP antagonists have been undergoing investigation as anxiolytics and antidepressants. However, sex differences have been reported in the response to KOP ligands both preclinically and clinically. Evidence showed that the gonadal hormones might be involved in the sex differences in the effect of KOP ligands. This project aims to investigate sex differences in the response to kappa ligands in rodents to ultimately achieve a better understanding of their therapeutic efficacy and potential for side effects in patients.

Firstly, we found a sex difference in the pharmacokinetic profile of the KOP agonist U50,488. In C57BL/6 mice, but not in CD-1 mice, males showed higher serum concentration 30 and 60 min after treatment than in females. This was not reflected in brain levels nor in antinociceptive responses to U50,488 (10 mg/kg). However, at 60 min after treatment, U50,488 showed an antinociceptive effect in male CD-1 mice but not in females, with no difference in serum or brain concentrations. No sex difference was found in serum or brain concentrations or in the antinociceptive effect of the clinically useful analgesic, buprenorphine (1 mg/kg). Secondly, we showed in Sprague Dawley rats that an injectable, prolonged-release depot formulation of buprenorphine (PRL-BUP) produced sustained kappa antagonism for at least three days following administration. In contrast, a single dose of buprenorphine (0.45 mg/kg) produced transient KOP antagonism 1h post administration that was not evident 20h post administration. There were no evident sex differences in the effects of PRL-BUP. Future experiments will investigate whether the prolonged KOP antagonism produced by PRL-BUP has antidepressant or anxiolytic actions that might explain enhanced clinical outcomes for patients treated with long-acting formulation of buprenorphine for opioid use disorder.

Finally, we developed a 3-day repeated predator odour exposure stress paradigm in C57BL/6 mice. Sex differences were found only in plasma corticosterone levels being higher in female, than in male, C57BL/6 mice before and after repeated exposure to synthetic fox odour (2,5-dihydro-2,4,5-trimethylthiazole, TMT). Daily exposure for 3 days to TMT (10 µl, 100%) for 10 min produced avoidance behaviours, elevated corticosterone levels and produced a stress-adaptive change in behaviour in the forced swim test (approximately 2-fold increase in the time spent immobile). No change in sucrose preference was evident after 3-days repeated TMT exposure. Additionally, the tricyclic antidepressant desipramine (10 mg/kg) and KOP antagonists naltrexone (1mg/kg) and BU10119 (1 mg/kg) reversed the 3-day predator odour exposure stress-induced behaviour change in the forced swim test suggesting antidepressant-like effects of naltrexone and BU10119 in stressed mice.

Date of Award	25 Jun 2025
Original language	English
Awarding Institution	University of Bath
Supervisor	Sarah Bailey (Supervisor) & Stephen Husbands (Supervisor)