Estradiol protects against pain-facilitated fentanyl use via suppression of opioid-evoked dopamine activity in males

Highlights•Inflammatory pain increases fentanyl self-administration selectively in males•VTA dopamine neuron response magnitude drives the magnitude of fentanyl use•Estradiol's effects on fentanyl use and dopamine activity are pain-context dependent•Estradiol suppresses fentanyl-evoked VTA dopamine in intact rats via ERβSummaryPain relief is the most frequently reported motivation for opioid misuse, but it remains unclear how pain alters reward pathway function contributing to maladaptive opioid use and whether these neuroadaptations occur in a sex-specific manner. Here, we show that persistent inflammatory pain leads to augmented fentanyl self-administration in male, not female, rats. Wireless in vivo fiber photometry recordings and chemogenetic manipulations indicate that pain-facilitated fentanyl use is mediated by enhanced ventral tegmental area dopamine (VTADA) neuron responses during self-administration. In females, ovariectomy enhances fentanyl self-administration, but the protective effects of ovarian hormones are not solely mediated by estradiol per se. Instead, pain and high estradiol states—naturally occurring in intact females or artificially produced in males—suppress fentanyl self-administration and associated VTADA activity through VTA estrogen receptor beta signaling. These findings highlight the importance of assessing hormonal factors in opioid misuse liability in the context of pain.Graphical abstract