Dissecting the Effects of Different Pain Modalities and Oxycodone on Prodynorphin Expressing Neurons in the Mouse Prelimbic Cortex

Abstract

Currently, changes to endogenous opioid circuits in various pain modalities, including surgical and neuropathic pain, remain unclear. Dynorphin, which is released by prodynorphin-expressing neurons (Pdyn+ neurons), is the endogenous opioid ligand to kappa opioid receptors (KOR). Moreover, a recent study has shown an increase in prodynorphin (Pdyn) mRNA expression in the prelimbic cortex (PL) in a mouse model of chronic pain. However, alterations in the activity of PL Pdyn-expressing neurons (PLPdyn+ neurons) in postoperative and chronic pain have never been explored. Firstly, I found that the population of PLPdyn+ neurons consists of both pyramidal and inhibitory subtypes. Secondly, I found that one day after surgical incision of the mouse hind paw, the excitability of pyramidal PLPdyn+ neurons was increased in both male and female mice, while the excitability of inhibitory PLPdyn+ neurons was unchanged. However, when postoperative pain behavior subsided, inhibitory PLPdyn+ neurons were hyperexcitable in male mice, while pyramidal PLPdyn+ neurons were hypoexcitable in female mice. Lastly, I dissected electrophysiological changes to PLPdyn+ neurons in the spared nerve injury (SNI) model of chronic neuropathic pain. At both early and late stages of SNI pain development, increased excitability of pyramidal PLPdyn+ neurons was detected in both male and female mice. However, in both male and female mice, the excitability of inhibitory PLPdyn+ neurons decreased 3 days after SNI but was conversely increased when measured 14 days after SNI. My findings suggest that different subtypes of PLPdyn+ neurons manifest distinct alterations in the development of different pain modalities in a sex-specific manner.