PROJECT SUMMARY
Opioid Use Disorder (OUD) is a chronic, relapsing disease that, despite our best efforts to understand and
mitigate the disease, has become a worsening public health crisis. 1,2 Currently, the medications to treat OUD
interact directly with opioid receptors. 3 While this helps patients decrease the use of more dangerous opioids,
the mechanism of action of the currently available drugs continues to perpetuate the substance abuse cycle.
Exploring novel non-opioid targets is necessary to overcome this current standstill. One specific alternative
population we are interested in investigating is calcitonin gene-related peptide (CGRP) expressing neurons
within the parabrachial nucleus (CGRPPBN). These neurons have been well studied in itch and pain fields and
are known to project to the central amygdala (CeA) 4,5, a brain region directly implicated in processing the
negative emotional valence associated with alcohol and opioid withdrawal. The objective of this proposal is to
assess the functional role of CGRPPBN in opioid reinforcement and to determine the gene expression and
epigenetic changes associated with opioid taking and opioid withdrawal. Our preliminary results show that
CGRPPBN activity decreases during opioid taking and increases during opioid withdrawal. We have also found
that this population of neurons robustly expresses the µ-opioid receptor along with glutamatergic markers,
positioning this population as a potential direct activator of the CeA during opioid withdrawal. To further probe
these results, I will inhibit CGRPPBN neurons using molecular and pharmacological approaches and determine
the behavioral consequences of these interventions. One of the pharmacological approaches we will be testing
is an FDA-approved CGRP inhibitor currently used for migraine treatment. We will then establish the molecular
profile of these neurons using nuclear RNAseq and Cleavage Under Tagmentation (CUT&Tag) at baseline, as
well as during morphine taking and protracted abstinence. By integrating transcriptomic data with epigenetic
information on post-translational histone modifications, I will be able to build a comprehensive map of the active
and inactive chromatin regions with their corresponding differentially expressed genes, which can be used to
detect epigenetic targets critical to the identity of CGRPPBN neurons. The results of this study will allow us to
establish the feasibility of targeting these neurons to treat OUD via currently FDA-approved medications or
through novel epigenetic targets identified in this study. These results will broaden our understanding of
withdrawal and help expand our therapeutic arsenal for the long-term maintenance of opioid abstinence and
prevention of relapse.