Neuropathic pain has sex-specific effects on oxycodone seeking and drug-seeking ensembles in the dorsomedial prefrontal cortex

Approximately 50 million Americans suffer from chronic pain, and opioids are commonly prescribed for such individuals. Unfortunately, nearly a quarter of chronic pain patients have reported misusing their prescription. We are investigating the effect of chronic pain on drug-seeking behavior at the neuronal level. Repeated drug-seeking is associated with reactivation of an ensemble of neurons sparsely scattered throughout the dorsomedial prefrontal cortex (dmPFC). Prior research has demonstrated that chronic pain increases intrinsic excitability of dmPFC neurons, which may increase the likelihood of reactivation during drug seeking. We tested the hypothesis that chronic pain would increase oxycodone seeking behavior, and that the pain state would differentially increase intrinsic excitability in dmPFC drug seeking ensemble neurons. TetTag mice self-administered intravenous oxycodone. After 7 days of forced abstinence, a drug seeking session (extinction conditions) was performed and the ensemble was tagged. Mice received spared nerve injury (SNI) to induce chronic pain during the period between a first and second seeking session, and we measured persistence of seeking between the two sessions to determine if the SNI exacerbated seeking. Following the second seeking session we performed electrophysiology on individual neurons within the dmPFC to assess intrinsic excitability of the drug-seeking ensemble and non-ensemble neurons. We found significant sex differences in the effect of SNI on oxycodone seeking and electrophysiology, such that the induction of chronic pain could modulate seeking behavior in mice that have previously self-administered oxycodone prior to injury. HighlightsO_LIOxycodone seeking was higher in females following SNI that came after the 10-day SA timeline. C_LIO_LIAn increase in intrinsic excitability was detected among non-ensemble neurons from female mice that received SNI, and this correlated with an increase in seeking behavior. C_LI