# Dissecting the role of mPFC dynorphin circuits in the modulation of different pain states

> **NIH NIH UF1** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $2,068,842

## Abstract

PROJECT SUMMARY
The goal of this work is to identify pain-induced adaptations in the prefrontal cortical dynorphin / kappa-opioid
receptor system and the role this system plays in pain-induced mal-adaptive behavior and nociception. Chronic
pain drives adaptations in prefrontal cortical circuits and is hypothesized to increase bias towards aversive
experiences. Our preliminary data demonstrates that inhibitory and excitatory populations of prefrontal cortical
dynorphin neurons are activated and release dynorphin neuropeptide in response to aversive stimuli. However,
it is unclear whether prefrontal cortical dynorphin neuron activity and ensuing dynorphin release is impacted by
pain. To address this knowledge gap, we will perform ex-vivo electrophysiological procedures and in-vivo single
cell calcium imaging in freely moving mice to determine how pain influences activity of excitatory and inhibitory
prefrontal cortical dynorphin neurons and their responsivity to noxious stimuli and aversive stimuli. Moreover, we
will manipulate the activity of prefrontal cortical dynorphin neurons and release of dynorphin neuropeptides or
fast transmitters to determine whether enhanced prefrontal cortical dynorphin neuron activity and transmitter
release controls nociception and mal-adaptive affective behavior induced by pain. Taken together, this work will
identify how genetically-defined sub-populations of prefrontal cortical neurons and the opioid peptides or fast
excitatory and inhibitory transmitters they release influence negative affect induced by pain from the cellular to
in-vivo level of analysis. This work is of broad relevance as it elucidates basic principles by which neuropeptide-
expressing neurons in prefrontal cortical circuits control behavioral plasticity and delineate potentially new
therapeutic targets for the treatment of mal-adaptive affect and increased responsivity to noxious and aversive
stimuli associated with pain states.

## Key facts

- **NIH application ID:** 10868896
- **Project number:** 1UF1NS132920-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Patrick L Sheets
- **Activity code:** UF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,068,842
- **Award type:** 1
- **Project period:** 2024-09-20 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868896

## Citation

> US National Institutes of Health, RePORTER application 10868896, Dissecting the role of mPFC dynorphin circuits in the modulation of different pain states (1UF1NS132920-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10868896. Licensed CC0.

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