# Determining the impact of BNST CRF systems on inflammatory pain-induced disruptions of behavior

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $431,179

## Abstract

Pain is currently the most common cause of long-term disability in the United States, affecting over 70 million
Americans and 1.5 billion people worldwide. The first line of treatment for pain has been opioids, however their
use is associated with addiction, dependence and overdose. A strategy for reducing the reliance on opioids for
treatment of chronic pain is to better understand the circuits that mediate different aspects of chronic pain and
identify non-opioidergic mechanisms to restore normal circuit function and behavior. Corticotropin releasing
factor (CRF) signaling in the bed nucleus of the stria terminalis (BNST) has been shown to regulate both
nociceptive and affective/motivational behaviors associated with pain, however the clinical utility of
pharmacologically targeting the CRF system has yet to be explored. Given the critical need to develop treatments
to target affective and motivational aspects of chronic pain, this could be an important path forward. We
hypothesize that persistent inflammatory pain leads to increased activation of CRF signaling in the BNST leading
to disrupted affective behaviors and reduced motivation. We posit that modulators of BNST function that oppose
CRF signaling could provide a novel approach to investigate and treat both nociceptive and motivational/affective
aspects of pain. Relevant to this, we have found in preliminary studies, a population of periaqueductal gray
dopamine (PAGDA) neurons that project to the BNST that exhibit anti-nociceptive properties when activated,
highlighting the possibility that dopamine in the BNST is a critical suppressor of pain-related behaviors. Previous
studies have found that these PAGDA neurons play a key role in opioid induced anti-nociception. The objective
of this proposal is to rigorously and mechanistically determine the role of the PAGDA to BNSTCRF circuit in
inflammatory pain-driven changes in behavior, with the long term goal of identifying new treatments for
inflammatory pain. We have collected strong data showing that acute pain engages this circuit, and hypothesize
that this initial engagement leads to plasticity contributing to the persistence of inflammatory pain, and the
development of emotional behaviors associated with inflammatory pain. This will be accomplished via three
convergent aims

## Key facts

- **NIH application ID:** 10233034
- **Project number:** 1R01NS122230-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Thomas L. Kash
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $431,179
- **Award type:** 1
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10233034

## Citation

> US National Institutes of Health, RePORTER application 10233034, Determining the impact of BNST CRF systems on inflammatory pain-induced disruptions of behavior (1R01NS122230-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10233034. Licensed CC0.

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