SEX-DEPENDENT EFFECTS OF THE KAPPA OPIOID RECEPTOR BIASED AGONIST NALFURAFINE ON PHASIC DOPAMINE RELEASE IN RATS

Biological sex shapes vulnerability to neuropsychiatric disorders, including opioid use disorder and mood disorders. Males and females differ in the behavioral effects of opioids as well as opioid modulation of mesolimbic dopamine activity. In particular, females are less sensitive to the effects of kappa-opioid receptor (KOR) activation, which mediates negative affect and depressive-like behaviors. Nalfurafine, a biased KOR agonist, is a novel analgesic with diminished side effects such as sedation and dysphoria. Importantly, nalfurafine effects on mesolimbic dopamine activity in males and females remain unexplored. We aimed to determine whether nalfurafine modulates dopamine release in the mesolimbic system as well as to establish potential sex-based differences in these effects. Phasic dopamine release was measured using fast-scan cyclic voltammetry in urethane-anesthetized Sprague-Dawley male and female rats. Dopamine release was evoked by electrical stimulation of the ventral tegmental area (VTA) and recorded in the nucleus accumbens (NAc). Nalfurafine was administered intraperitoneally or into the VTA to assess its effects on dopamine release. Nalfurafine attenuated phasic dopamine release in the NAc in males and females. However, females required higher doses of nalfurafine to achieve comparable modulation of dopamine signaling, indicating reduced sensitivity to KOR activation. Our results suggest sex-dependent differences in responsiveness to biased KOR agonism. In conclusion, we demonstrated that biased opioid nalfurafine is a potent modulator of mesolimbic dopamine signaling, however, in a sex-dependent manner, further emphasizing sex as a biological variable in opioid related neural circuit research and its relevance in the clinic. Funding: NationalScienceCentre: UMO-2020/39/B/NZ7/03537