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.

NARRATIVE There is a desperate need for efficacious, safe and misuse free analgesics. Based on its understudied nature, druggability and known association with pain modulation, we will explore the plausibility of the GCH1 gene product GTP Cyclohydrolase 1 as a target for treating chronic orofacial pain.