Estradiol Protects Against Pain-Facilitated Fentanyl Use Via Suppression of Opioid-Evoked Dopamine Activity in Males

Pain affects over 50% of US adults. Opioids are potent analgesics used to treat pain symptoms but are highly prone to abuse, creating a major dilemma for public health. Evidence suggests that the risk for opioid misuse under conditions of pain may vary based on gender/sex, but the biological basis of this relationship is unclear. Here, we characterize the effects of pain on fentanyl use and decipher its underlying mechanisms within mesolimbic dopamine reward circuitry, providing evidence for regulation by ovarian hormones. Using wireless in vivo fiber photometry, we reveal that pain time-dependently enhances fentanyl self-administration selectively in male rats by enhancing opioid-evoked responses from ventral tegmental area dopamine (VTA-DA) neurons terminating in the nucleus accumbens (NAc). Using chemogenetics, we show that high-amplitude fentanyl-evoked VTA-DA transient events are necessary to drive excessive fentanyl use in males. Moreover, ovarian hormones protect females from pain-facilitated VTA-DA dynamics and fentanyl self-administration, but these effects are not attributable to estradiol per se. Instead, we demonstrate the therapeutic potential of systemic estradiol treatment in males, and the ability of estradiol to reverse the effects of pain on VTA-DA function and fentanyl use. Finally, we show that VTA estrogen receptor beta, not alpha, plays a critical role in modulating the suppressive effects of estradiol. These findings are the first to implicate a role for gonadal hormones in pain-facilitated opioid use and provide novel therapeutic targets within the mesolimbic DA reward circuitry that may contribute to pain-related motivational states and risk for opioid abuse.