# Targeting GTP Cyclohydrolase 1 for treating chronic orofacial pain

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2024 · $27,063

## Abstract

PROJECT SUMMARY
 Chronic pain is a global healthcare problem that reduces the quality of patients’ lives and increases med-
ical expenditures. Inadequate pain control with available treatments indicates a need to understand mechanisms
underlying the pathogenesis to develop novel treatment strategies in chronic pain. The GHC1 gene (Gch1 in
rodents) encodes GTP cyclohydrolase 1 (GTPCH1). GTPCH1 is the rate-limiting enzyme in tetrahydrobiopterin
(BH4) synthesis which is an essential cofactor for catecholamine (dopamine, norepinephrine, and epinephrine),
serotonin, and nitric oxide production. Alterations in Gch1 gene expression are implicated in the development
and maintenance of inflammatory and neuropathic pain in rodents. Genetic mutations in the GCH1 gene are also
linked with pain perception in humans. Thus far, evidence regarding the role of Gch1 in chronic pain has come
from animal models of sciatic nerve injury-induced neuropathic pain, cancer, or visceral pain and these studies
have focused on the role of Gch1 in the peripheral nervous system. To date, no study has investigated the role
of Gch1 in a chronic orofacial neuropathic pain model and no study has investigated Gch1 in reward and brain
regions involved in pain modulation and reward. We hypothesize that orofacial neuropathic pain increases the
expression of Gch1 in trigeminal ganglia and central pain- and reward-related pathways, and inhibition of
GTPCH1 via the GTP cyclohydrolase inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) will alleviate nerve in-
jury-induced pain responses concordant with altering Gch1 gene expression and monoamine turnover in the
brain and the periphery. As there is legitimate concern that any novel analgesic could have misuse potential, we
will also study the motivating and rewarding effects of DAHP in naïve and chronic pain conditions. Here we
hypothesize that DAHP acquires rewarding properties only in a chronic pain state. We will address these ques-
tions using an operant orofacial pain assay, an orofacial neuropathic pain model induced by chronic constriction
injury of the infraorbital nerve, targeted molecular methods and place conditioning behavior in rats. Data gener-
ated from the current application is expected to provide avenues towards new non-addictive safe treatment
strategies for the management of chronic pain via modulation of GTPCH1.

## Key facts

- **NIH application ID:** 10844705
- **Project number:** 1R21DE033640-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Basak Ayaz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $27,063
- **Award type:** 1
- **Project period:** 2024-09-11 → 2025-02-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844705

## Citation

> US National Institutes of Health, RePORTER application 10844705, Targeting GTP Cyclohydrolase 1 for treating chronic orofacial pain (1R21DE033640-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10844705. Licensed CC0.

---

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