Mouse models of surgical and neuropathic pain produce distinct functional alterations to prodynorphin expressing neurons in the prelimbic cortex

The medial prefrontal cortex (mPFC) consists of a heterogeneous population of neurons that respond to painful stimuli, and our understanding of how different pain models alter these specific mPFC cell types remains incomplete. A distinct subpopulation of mPFC neurons express prodynorphin (Pdyn(+)), the endogenous peptide agonist for kappa opioid receptors (KORs). Here, we used whole cell patch clamp for studying excitability changes to Pdyn expressing neurons in the prelimbic region of the mPFC (PL(Pdyn+) neurons) in mouse models of surgical and neuropathic pain. Our recordings revealed that PL(Pdyn+) neurons consist of both pyramidal and inhibitory cell types. We find that the plantar incision model (PIM) of surgical pain increases intrinsic excitability only in pyramidal PL(Pdyn+) neurons one day after incision. Following recovery from incision, excitability of pyramidal PL(Pdyn+) neurons did not differ between male PIM and sham mice, but was decreased in PIM female mice. Moreover, the excitability of inhibitory PL(Pdyn+) neurons was increased in male PIM mice, but was with no difference between female sham and PIM mice. In the spared nerve injury model (SNI), pyramidal PL(Pdyn+) neurons were hyperexcitable at both 3 days and 14 days after SNI. However, inhibitory PL(Pdyn+) neurons were hypoexcitable at 3 days but hyperexcitable at 14 days after SNI. Our findings suggest different subtypes of PL(Pdyn+) neurons manifest distinct alterations in the development of different pain modalities and are regulated by surgical pain in a sex-specific manner. Our study provides information on a specific neuronal population that is affected by surgical and neuropathic pain.