µ-Opioid receptor antagonism facilitates the anxiolytic-like effect of oxytocin in mice

Abstract

Mood and anxiety disorders are leading causes of disability worldwide and are major contributors to the global burden of diseases. Neuropeptides, such as oxytocin and opioid peptides, are important for emotion regulation. Previous studies have demonstrated that oxytocin reduced depression- and anxiety-like behavior in male and female mice, and opioid receptor activation reduced depression-like behavior. However, it remains unclear whether the endogenous opioid system interacts with the oxytocin system to facilitate emotion regulation in male and female mice. We hypothesized that opioid receptor blockade would inhibit the anxiolytic- and antidepressant-like effects of oxytocin. In this study, we systemically administered naloxone, a preferential μ−opioid receptor antagonist, and then intracerebroventricularly administered oxytocin. We then tested mice on the elevated zero maze and the tail suspension tests, respective tests of anxiety- and depression-like behavior. Contrary to our initial hypothesis, naloxone potentiated the anxiolytic-like, but not the antidepressant-like, effect of oxytocin. Using a selective μ−opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, and a selective κ−opioid receptor antagonist, norbinaltorphimine, we demonstrate that μ−opioid receptor blockade potentiated the anxiolytic-like effect of oxytocin, whereas κ−opioid receptor blockade inhibited the oxytocin-induced anxiolytic-like effects. The present results suggest that endogenous opioids can regulate the oxytocin system to modulate anxiety-like behavior. Potential clinical implications of these findings are discussed.

Indulging Curiosity: Preliminary Evidence of an Anxiolytic-like Effect of Castor Oil and Ricinoleic Acid

“…The mice were kept in a room with a 12 h/12 h light/dark cycle (lights on at 7 AM) with controlled temperature (22 • C ± 2 • C) and humidity (50-60%). Behavioral testing occurred during the light cycle following previously reported experimental conditions that allow for the detection of anxiolytic-and anxiogenic-like effects [26,27]. The mice were randomly assigned to experimental groups.…”

“…The mice were randomly assigned to experimental groups. Sample sizes (n = 8-16) were determined based on our previous publications to ensure adequate power to detect statistical differences [26,27]. No animals were excluded from the study.…”

The oxytocin system in patients with craniopharyngioma: A systematic review

“…The difference in effects of oxytocin on BMI/ weight here may be accounted for by the addition of naltrexone (100mg/day) over the treatment period in Hsu et al (2017). Naltrexone is an opioid antagonist with selective preference for μ-opioid receptor binding that has shown to be an effective treatment for adult obesity (Kulak-Bejda et al, 2021); μ-opioid receptor antagonism has shown to potentiate the effects of oxytocin (Nisbett et al, 2024) and increase plasma oxytocin concentrations by disinhibition of central oxytocin release in rodents during late pregnancy (Douglas et al, 1993). However, Hsu et al (2017) did report a decrease in BMI z-score from 1.77 SDS to 1.49 SDS (93 rd percentile) over the 10 weeks before naltrexone was added.…”