The Pharmacology of GPR171 Ligands in the Treatment of Pain: An In Vitro and In Vivo Preclinical Characterization

Opioids are addictive, ineffective for long-term treatment, readily produce withdrawal and tolerance, and can cause overdose and death. These properties have contributed to an epidemic of addiction and overdose, which continues unabated in the United States. Therefore, new drugs to treat acute and chronic pain are needed. Opioids bind to receptors belonging to a superfamily of proteins called G protein-coupled receptors (GPCRs). GPCRs are the most commonly targeted proteins among FDA-approved drugs. As such, under-researched GPCRs are a viable source of new targets in the field of drug development. One such underexplored GPCR is GPR171. Studies have demonstrated that a drug for GPR171 reduces pain in mice subjected to chronic and acute pain conditions. The goal of this current work was to explore further this receptor's potential to treat pain. To do this, I first tested the ability of GPR171 drugs to affect opioid analgesia in mice. I show that one drug, called MS15203, increases morphine analgesia in mice. Next, I assessed if MS15203 activates a region of the brain associated with pleasure and addiction and whether it increases addiction-like behaviors in mice. I show that MS15203 does not activate this brain region and fails to elicit addiction-like behaviors. Lastly, I tested several new potential GPR171 drugs in cultured brain cells to assess their impact on two cellular pathways: G protein signaling and β-arrestin signaling. I found that two new drugs, compounds 5 and 7, activate G protein signaling more than MS15203. This is a promising result because opioid drugs that activate G protein signaling more than β-arrestin signaling (e.g., morphine) have increased analgesia and lessened side effects than opioids that favor β-arrestin signaling (e.g., fentanyl). These experiments demonstrate that MS15203 enhances the pain-relieving effects of morphine with minimal risk of addiction. Additionally, I identify two potential GPR171 drugs that preliminary data suggests may be more effective than MS15203. This work contributes to the growing body of evidence that targeting GPR171 with GPR171 drugs holds promise for the treatment of pain.