Time-dependent enhancement in ventral tegmental area dopamine neuron activity drives pain-facilitated fentanyl intake in males

Abstract

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 proclivity for opioid abuse under pain conditions varies between sexes. However, the neural mechanisms underlying sex-specific effects of pain on opioid use are largely unclear. Here, we recapitulate clinical findings and demonstrate that pain increases self-administration of the widely abused opioid, fentanyl, selectively in male rats. These behavioral effects develop over time and are paralleled by sex- and pain-specific effects on fentanyl-evoked ventral tegmental area (VTA) dopamine (DA) neuron activity, a critical mediator of motivation and reward. Using in vivo fiber photometry, we show that tonic VTA DA neuron activity is attenuated in males with pain. In contrast, phasic VTA DA neuron responses to self-administered fentanyl increase in magnitude at later timepoints and correspond with increases in fentanyl intake. The protracted increase in fentanyl-evoked VTA DA activity is necessary for pain to enhance fentanyl self-administration in males because chemogenetic inhibition of VTA DA neurons normalized fentanyl intake and associated fentanyl-evoked VTA DA neuron responses. These findings reveal time-dependent and sex-specific pain-induced adaptations to VTA DA neuron function that underlie maladaptive patterns of opioid use.

Protracted morphine withdrawal corresponds with sex-specific alterations to motivated behavior and mesoaccumbal subcircuit dopamine cell plasticity

“…Regarding mesoaccumbal circuitry, a sex-and time-dependent adaptation to VTA DA cell activity has been reported by Jones and colleagues, with opioid-evoked phasic activity of DA cells bidirectionally changing across a three-week period of opioid exposure in males 59 .…”

“…Regarding mesoaccumbal circuitry, a sex- and time-dependent adaptation to VTA DA cell activity has been reported by Jones and colleagues, with opioid-evoked phasic activity of DA cells bidirectionally changing across a three-week period of opioid exposure in males 59 . Additionally, Jones and colleagues have shown that long-access heroin self-administration enhances phasic DA release in the medial NAc shell but not core subregion in females, with males displaying no difference in either subregion 53 .…”

“…For instance, females are believed to be more sensitive to stress- and drug cue-induced opioid relapse compared to males 57,58 . On the other hand, males may be more prone to pain motives relating to opioid intake, with evidence suggesting they are more sensitive to hyperalgesia following opioid withdrawal and more likely to escalate opioids in response to pain 43,44,59 . And morphine has been found to induce divergent affective states between sexes, with males reporting greater positive and females greater negative subjective mood-altering effects following acute injection 60 .…”

Inflammatory pain affects alcohol intake in a dose-dependent manner in male rats in the intermittent access model

“…These sex differences seem to be in accordance with a recent report showing that pain does not alter the dose response for fentanyl self-administration in female rats. 12 Previous studies have shown differential effects of pain on drug seeking in a sex-dependent manner. 12 , 30 Therefore, it is likely that similar pain-induced sex-dependent effects may be observed in alcohol drinking behaviors.…”

Pattern of Self-Administered Vapor Fentanyl Exposure Determines Long-term Behavior Consequences, in Mice with or without Neuropathic Pain

“…We observed an interaction of chronic pain and sex on opioid motivation, in which SNI females showed greater motivation for opioids with increasing effort. Other work with a complete Freund's adjuvant injury led to increased intravenous fentanyl self-administration in male, but not female rats [47], while exposure to morphine shows no difference during the acquisition phase between SNI and sham animals [44]. However, authors looking at various intravenous opioids, including fentanyl, found that male rats with a spinal nerve ligation self-administered less than sham animals at lower doses, but similar amount of infusions at higher doses [12].…”