# Dissecting the contribution of glutamatergic ventral pallidal neurons to the aversive state of opioid withdrawal

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2024 · $34,908

## Abstract

PROJECT SUMMARY
Opioid use disorder is an urgent public health crisis in the U.S. and roughly 30% of Americans prescribed opioids
misuse their medications. The overwhelming reason people with opioid use disorder continue taking opioids is
to avoid withdrawal. Opioid withdrawal is physically painful and emotionally exhausting. Despite the inherently
chronic relapsing nature of drug abuse and withdrawal, studies of how long-term opioid use alters the aversion
circuits of the brain are surprisingly limited compared to those studying the reward circuits. Dysfunction of
mesolimbic circuits, which includes the ventral pallidum (VP) and its downstream targets, has been implicated
in a wide range of substance abuse disorders, including opioid use disorder, but it is not known how opioid use-
induced adaptations arise in these brain areas. One hypothesis is that withdrawal from chronic use of opioids
may prompt adaptations in aversion-processing circuits that generate a higher sensitivity to aversive stimuli and
mediate the general negative affective state associated with withdrawal; thus leading to increased stress and
subsequent relapse. The VP is especially well-positioned to mediate adaptations of aversion circuits in opioid
use disorder. VP neurons receive input from reward and aversion encoding structures and modulate aversion
centers of the brain, a primary output being the lateral habenula (LHb). Furthermore, a recently discovered subset
of VP neurons (VPGlu) has been shown to encode aversion in reward-related contexts. In this proposal, I plan to
use a multi-faceted approach to investigate opioid use-induced adaptations of LHb-projecting VP (VPGluLHb)
neurons in mice. I hypothesize that VPGlu neurons are hyperactive and more responsive to noxious stimuli in
protracted opioid withdrawal, and that opioid withdrawal potentiates transmission at VPGluLHb synapses.
Lastly, I expect that VPGlu neuronal activity confers sensitivity to negative outcomes and that this response is
heighted following opioid withdrawal. I propose to test each of these hypotheses in specific aims using in vivo
and ex vivo electrophysiology, optogenetics, and behavioral techniques to evaluate VPGluLHb activity and
plasticity as potential mechanisms underlying enhanced sensitivity to aversive outcomes and events. Successful
completion of these aims will inform future therapeutic interventions to treat the negative affective state of opioid
withdrawal to allow for successful treatment of opioid use disorder.

## Key facts

- **NIH application ID:** 10806177
- **Project number:** 5F31DA056194-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jessica Tooley
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,908
- **Award type:** 5
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806177

## Citation

> US National Institutes of Health, RePORTER application 10806177, Dissecting the contribution of glutamatergic ventral pallidal neurons to the aversive state of opioid withdrawal (5F31DA056194-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10806177. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*