# Dissecting circuits mediating pain-induced alterations in motivated behavior

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $456,028

## Abstract

Maladaptive pain-induced dysfunction in motivational circuits are the likely critical factors that lead to
pathological alterations in natural and drug reward seeking behaviors, yet the neural circuit mechanisms for
these effects are largely unknown. The mesolimbic system is a key network node that integrates pain and
reward. Dopamine (DA) transmission in the mesolimbic system, via the VTA to NAc has long been recognized
for its role in motivated behavior. Alterations in DA signaling within the mesolimbic pathway are associated with
motivational deficits, and animals in pain show impaired motivated responses to natural and drug reward.
Importantly, from a translational perspective, negative correlations between pain and mesolimbic DA activity in
humans have been often reported. Mu opioid receptor (MOPR) agonists are positively reinforcing and remain
the predominant opioids used for alleviating clinical pain and recreational use/abuse. We recently found that
persistent inflammatory pain downregulates function of MOPR in the VTA with a concomitant loss of opioid-
induced DA release in the NAc in a dose-dependent manner leading to increase intake of higher doses of
opioids which are known to contribute to abuse-associated phenotypes. In addition, our preliminary data
suggest that persistent inflammation causes an increase in endogenous opioid tone which is likely leading to
desensitization of MOPR in the VTA. Collectively, these findings suggest that pain suppresses VTANAc
neural circuit activity through suppression of mesolimbic DA release. We predict that this effect is mediated by
an increase in endogenous opioid tone and reduction of MOPR function in the VTA which negatively impact
the animal's motivational state contributing to an opioid abuse-associated phenotype. In this application we
propose cross disciplinary cutting-edge approaches to dissect the neuronal and cellular mechanisms
underlying the downregulation of mu-opioid circuits in the presence of inflammatory pain. In three specific
aims we will: i) determine the mechanisms for downregulation of mu-opioid-containing GABAergic circuits in
inflammatory pain ii) determine whether increases in endogenous mu-opioid agonist tone changes mu-opioid
function, and whether these processes are necessary and sufficient for the effects of inflammatory pain on
motivated behavior. Finally, in a third aim we will directly visualize endogenous opioid-containing neuronal
ensembles during the development of inflammatory pain and decreased motivational states. Here we will
determine whether mu-opioid receptors, their endogenous agonists, within discrete mesolimbic neural circuits,
are necessary and sufficient to mediate pain-induced alterations in opioid intake and motivated behavior.

## Key facts

- **NIH application ID:** 9828088
- **Project number:** 5R01DA041781-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jose A Moron-Concepcion
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $456,028
- **Award type:** 5
- **Project period:** 2017-02-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828088

## Citation

> US National Institutes of Health, RePORTER application 9828088, Dissecting circuits mediating pain-induced alterations in motivated behavior (5R01DA041781-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828088. Licensed CC0.

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