Time-dependent enhancement in ventral tegmental area dopamine neuron activity drives pain-facilitated fentanyl intake 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 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/504549v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@830345org.highwire.dtl.DTLVardef@14be4d2org.highwire.dtl.DTLVardef@19bc8e5org.highwire.dtl.DTLVardef@a251fc_HPS_FORMAT_FIGEXP M_FIG C_FIG