# Targeting TRPV1-containing nerves for radiation-induced pain and oral mucositis

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $198,750

## Abstract

PROJECT SUMMARY
Pain during and after radiation therapy (RT) for head and neck cancer (HNC) is a major clinical challenge due
to its multifactorial etiology and variable management. In a recent clinical retrospective study of 351 HNC
patients, the majority (61%) undergoing RT reported ongoing “burning” pain by the end of treatment suggesting
a neuropathic pain phenotype. However, radiation-induced pain typically co-develops with oral mucositis (OM),
an inflammatory condition defined as tissue damage to the oral mucosa resulting in highly symptomatic lesions
that affect patients' function, quality of life, and ability to tolerate treatment. Effective pain treatment in HNC
patients receiving RT remains an important unmet clinical need; intermittent breaks taken due to pain often
result in poor therapeutic response and recurrence. Preclinical research efforts are needed to develop and
evaluate new therapeutic options; however, standardized preclinical RT-induced pain models are severely
lacking. Sensory innervation of the oral cavity is dense and TRPV1-expressing peptidergic afferents have been
strongly implicated in pain associated with both oral cancer and RT-induced OM. A recent study by Meneses et
al. found that systemic TRPV1 denervation reduced the severity of radiation-induced OM in a non-tumor
bearing mouse, however pain was not assessed. Furthermore, the impetus for this application is our
preliminary finding of a significant increase in S100-immunoreactive nerve density in tumor tissue 2 weeks
after mice received a single focal RT dose compared to sham radiation in 3 different HNC tumor models.
These results suggest that radiation by itself can induce neuronal sprouting in the oral cavity. This data
combined with previous evidence led to our hypothesis that both the pain and mucositis severity are due to the
negative synergy of radiation-induced sprouting acting on existing hyperinnervation induced by the tumor. The
critical prediction that follows from this hypothesis is that prophylactic denervation of the tumor prior to RT will
reduce both post-treatment pain and mucositis severity. To test this hypothesis, we will use a syngeneic
orthotopic transplant mouse model in tandem with single and multi-fraction RT to characterize nociceptive
behavior and OM as well as RT-induced primary afferent sprouting in vivo (Aim 1) and in vitro (Aim 2).
Additionally, we will use ultrapotent resiniferatoxin to denervate TRPV1-expressing sensory neurons prior to
RT to investigate if prophylactic denervation of the tumor prior to RT can reduce subsequent pain and OM
severity (Aim 3). We believe this proposal will begin to fill an important gap in knowledge in the cancer pain
field and allow for the development of new strategies to treat radiation-associated pain.

## Key facts

- **NIH application ID:** 10950683
- **Project number:** 1R21DE034106-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yvonne MARIE Mowery
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $198,750
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10950683

## Citation

> US National Institutes of Health, RePORTER application 10950683, Targeting TRPV1-containing nerves for radiation-induced pain and oral mucositis (1R21DE034106-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10950683. Licensed CC0.

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