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Parabrachial CGRP Neurons Regulate Opioid Reinforcement
Lauren L Bystrom1,2,3, Alexander V Margetts1,2,4, Nicole M Kujas1,2,4
1Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136.
Biorxiv : the Preprint Server for Biology
|March 27, 2026
Summary
Calcitonin gene-related peptide (CGRP) neurons in the brainstem modulate opioid reinforcement. Inhibiting these CGRP neurons reduced morphine intake, suggesting new therapeutic targets for opioid use disorder (OUD) beyond direct opioid receptor drugs.
Area of Science:
- Neuroscience
- Pharmacology
- Addiction Research
Background:
- Opioid use disorder (OUD) is a chronic relapsing disease with limited treatment options, necessitating novel therapeutic targets.
- Current OUD treatments primarily target the µ-opioid receptor, often causing side effects that limit efficacy.
- Calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) are implicated in modulating various behaviors, including those relevant to addiction.
Purpose of the Study:
- To investigate the role of CGRP-expressing neurons in the PBN (CGRP PBN neurons) in regulating opioid reinforcement and seeking.
- To explore the sensitivity of CGRP PBN neurons to opioid administration and their potential as novel therapeutic targets for OUD.
Main Methods:
- Generated a baseline transcriptome of CGRP PBN neurons using cell-specific nuclear labeling and RNA-sequencing.
- Assessed CGRP PBN neuron activity during morphine abstinence using cFos immunostaining.
- Utilized chemogenetics in a mouse model of morphine intravenous self-administration to inhibit CGRP PBN neuron activity and measure its effects on drug intake and seeking.
Main Results:
- CGRP PBN neurons express genes related to appetitive behaviors and the µ-opioid receptor, indicating sensitivity to opioids.
- Morphine abstinence increased CGRP PBN neuron activity, which gradually decreased over 48 hours.
- Chemogenetic inhibition of CGRP PBN neurons significantly reduced morphine intake but did not affect long-term, context-induced morphine seeking.
Conclusions:
- CGRP PBN neurons are sensitive to opioid administration and play a crucial role in regulating the appetitive aspects of morphine intake.
- Targeting CGRP neurotransmission, independent of direct µ-opioid receptor engagement, offers a promising novel therapeutic strategy for OUD.
- These findings highlight CGRP PBN neurons as potential targets for developing non-opioid-based treatments for opioid use disorder.
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