Circuit mechanisms for opioid analgesia and addiction in prefrontal cortex

PROJECT SUMMARY (ABSTRACT)
The mu opioid receptor (MOR) is widely expressed throughout the nervous system and mediates both analgesic
and addictive effects of opioids. Despite the current opioid crisis in the United States, opioid drugs offer
unparalleled analgesic efficacy and are prescribed for a variety of pain conditions. To dissociate opioid analgesic
and addictive effects, it is essential to determine which neural circuits and cell types mediate each of these
effects. MOR signaling in medial prefrontal cortex (mPFC) is of particular significance due to the mPFC function
as a key integrative node in ascending and descending pain circuits and its strong connectivity to subcortical
reward circuitry. However, how opioids eventually alter the activity of glutamatergic mPFC output neurons to
modulate opioid addiction and pain behaviors is unknown. The main outputs of the cortex include two distinct
populations of layer 5 glutamatergic projection neurons: intratelencephalic (IT) and pyramidal tract (PT) neurons.
IT neurons predominantly project intracortically and to striatum, while PT neurons project broadly and are poised
to directly modulate neural activity throughout the brain. Despite evidence supporting a MOR-dependent role for
mPFC in pain and addiction, preliminary data suggest that MOR is not expressed directly on IT or PT cells.
This project aims to (1) determine how opioid exposure impacts mPFC IT and PT cell activity in mice and (2)
delineate the contribution of mPFC IT and PT cells to opioid addiction and analgesia. In order to determine how
opioids modulate IT and PT cell activity, dual-color calcium imaging will be used as a proxy for neuronal activity.
Neural dynamics of each population will be characterized at baseline, during acute and chronic morphine
exposure through subcutaneously implanted pumps, and during naloxone-precipitated withdrawal. To assess
the contribution of IT and PT cells to opioid addiction, mPFC IT or PT cell activity will be chemogenetically
suppressed in addiction models including morphine conditioned place preference and oxycodone self-
administration. Finally, the contribution of IT and PT cells to morphine analgesia and opioid-induced tolerance
and hyperalgesia will be assessed through chemogenetic suppression of mPFC IT or PT cells after acute and
chronic morphine exposure in assays for thermal (hotplate) and mechanical (von Frey) pain. This project will
establish foundational knowledge in the dissociation of the addictive and analgesic effects of opioids,
illuminating targets for nonaddictive pain therapies.
Through this research proposal and associated training plan, I will gain excellent training in neuroanatomy,
addiction and pain behaviors, and neural dynamics in a supportive training environment at the University of North
Carolina MD/PhD Program. This training will provide me with the technical and professional skills necessary to
become a leader at an academic medical center and pursue my goals of practicing pain medicine and
researching innovative non-addictive therapies for pain as a physician-scientist.