Lauren L. Bystrom1,2,4, Alexander V. Margetts1-3, Nicole M. Kujas1-3, Florence M. Bourgain-Guglielmetti1-3, Elizabeth P. Marinov1-3 & Luis M. Tuesta1-3*
1 Department of Psychiatry & Behavioral Sciences 2 Center for Therapeutic Innovation 3 Sylvester Comprehensive Cancer Center 4 Medical Scientist Training Program University of Miami Miller School of Medicine, Miami, FL 33136
- Corresponding author (ltuesta@miami.edu)
- Site Maintainer (alexmargetts@med.miami.edu)
Opioid use disorder (OUD) is a chronic, relapsing disease driven by the reinforcing properties of opioids and perpetuated by avoidance of the negative affective states associated with withdrawal. While available OUD pharmacotherapies can be effective, there is an urgent need to identify novel therapeutic targets. One potential target is calcitonin gene-related peptide (CGRP). CGRP is a neuropeptide produced by a small population of neurons in the parabrachial nucleus (CGRPPBN). In this study, we use a virally mediated cell-specific isolation approach in combination with nuclear RNA-sequencing to establish the baseline transcriptome of CGRPPBN neurons in mice. Multiple genes related to appetite were highly enriched in CGRPPBN neurons, consistent with previous literature on the behavioral role of these neurons. Interestingly, CGRPPBN neurons also highly express the µ-opioid receptor, suggesting these neurons may be involved in opioid reinforcement. To this end, we show that CGRPPBN neurons are sensitive to morphine administration and withdrawal based on cFos staining, suggesting that this population may play a role in regulating the appetitive aspects of opioid taking. To test this hypothesis, we employed a dose-response model of morphine intravenous self-administration (IVSA) in mice, in which DREADD-mediated inhibition of CGRPPBN neurons decreased morphine intake at multiple morphine doses, but did not affect morphine tolerance or context-induced morphine seeking following prolonged abstinence. These data suggest CGRPPBN neurons play an important role in morphine reinforcement, possibly via appetitive control, and may therefore serve as a novel therapeutic target for OUD.
[Manuscript]
DP1DA051828; F30DA060666; and a kind gift from the Shipley Foundation.
[Manuscript]:
A workflowr project.