# The role of delta opioid receptors in trigeminovascular pain

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $456,209

## Abstract

Chronic use of commonly used migraine therapies can lead to medication overuse headache (MOH). This is a
paradoxical increase in severity of migraine-associated symptoms and headaches which are refractory to other
treatments. Currently, the first-line treatment for MOH is drug cessation. However, during this abstinence period,
patients continue to suffer from severe migraine, and a majority of MOH patients return to these medications
within the first year. Targeted therapies specifically for MOH would result in better headache management and
increased patient quality of life. One of the accomplishments of the previous funding cycle of this grant was to
test δ opioid receptor (δOR) agonists in multiple headache models, including models of MOH. We found that
δOR activation completely reversed cephalic allodynia induced by chronic medication treatment, revealing δOR
agonists as a novel therapeutic strategy for MOH. In the previous funding cycle, we also performed a large scale
unbiased peptidomic screen to identify overlapping mechanisms between chronic migraine and MOH. We
identified pituitary adenylate cyclase activating polypeptide (PACAP) binding through PAC1 receptor as a
potential link between these two disorders; and that the PACAPergic system may be distinctly involved in pain
facilitation by chronic medication exposure. Upon further analysis we also found that there is high co-expression
between δOR and PACAP or PAC1 in pain-processing regions, including in the periaqueductal grey (PAG) and
trigeminal complex. The overall goal of this renewal is to build upon these exciting findings and determine if δOR
agonists relieve migraine and MOH through inhibition of the PACAPergic system. In Aim 1, we will test G protein
biased δOR agonists in novel translationally significant models of cephalic MOH and determine if they cause
tolerance in this model. These studies will strengthen the evidence for drug development of δOR for MOH. In
Aim 2 we will map the co-expression of δOR with PACAP and PAC1 and use biochemical and
electrophysiological assays to investigate how δOR modulates PACAPergic signaling. Finally, in Aim 3 we will
generate conditional knockouts of δOR in PACAP and PAC1 expressing cells, which will reveal if the behavioral
effects of δOR agonists are regulated through PACAPergic signaling. The experiments proposed in this
application are highly innovative and use a multidisciplinary approach. They will provide important insight on the effectiveness of δOR agonist as a therapeutic target for MOH and headache disorders more broadly and will
determine if δOR agonists work through inhibition of the PACAPergic system. Further, the modulation of the
PACAPergic system by δOR may be fundamental to other δOR behavioral effects, including emotional
modulation and peripheral analgesia.

## Key facts

- **NIH application ID:** 10806179
- **Project number:** 5R01NS130882-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Amynah Amir Ali Pradhan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $456,209
- **Award type:** 5
- **Project period:** 2023-03-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806179

## Citation

> US National Institutes of Health, RePORTER application 10806179, The role of delta opioid receptors in trigeminovascular pain (5R01NS130882-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10806179. Licensed CC0.

---

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