Uncovering the role of neuropeptide receptor GPR83 in nociception

Abstract

Nociception, the perception of noxious stimuli, is a critical function for the sensation of pain that protects us from damaging ourselves and helps protect the body following an injury. While pain is important, many people suffer from chronic pain due to a dysregulation of the mechanisms that detect noxious stimuli. G‐protein coupled receptors (GPCRs) are critical regulators of cell function making them frequent targets of therapeutic agents. The recent identification of the neuropeptide PEN as an endogenous ligand for the GPCR, GPR83, opens the possibility of exploring the neurobiological function of this receptor. Recent studies have provided evidence that GPR83 is expressed in a specific ascending spinal tract and that these neurons are highly sensitive to mechanical stimuli. New tools to study GPR83 include small molecule agonists and antagonists. Using these compounds, we have identified that GPR83 agonists blunt morphine antinociception while antagonists enhance morphine antinociception. Since morphine is the most effective therapeutic for pain this suggests that GPR83 is involved in the pain pathway however, it is unknown whether there is a direct impact of GPR83 on nociception. Moreover, the potential of targeting GPR83 to alleviate chronic pain has not been investigated. We have preliminary data suggesting that GPR83 antagonists increase sensitivity to mechanical stimuli while having no impact on thermal stimuli. Our study aims to further characterize GPR83’s role in nociception and to identify whether this receptor has any direct impact on pain itself, using the Complete Freud’s Adjuvant (CFA) model of inflammatory pain.