Chronic pain is a debilitating condition leading to impaired quality of life but has few efficacious therapeutic options. The use of opioids to treat chronic pain is associated with well‐known drawbacks including drug dependence and addiction. The development of opioid alternatives to treat chronic pain is an urgent, yet unmet, need. Here we show the therapeutic potential of GPR171, a G‐Protein Coupled Receptor that was recently identified to regulate morphine antinociception. Previously shown that systemic administration of the GPR171 agonist, MS15203, enhances morphine antinociception in acute pain tests in mice. Here, we show that once‐daily systemic administration of MS15203 (10 mg/kg, i.p.) over the course of 1 week improved chronic pain outcomes in two different mouse pain models. Chemotherapy‐induced peripheral neuropathy (CIPN) was induced by injecting Paclitaxel (16 mg/kg cumulative) and inflammatory pain was induced by injecting Complete Freund’s Adjuvant (CFA) under the epidermis into the plantar surface of both hind paws (20 µl/paw). MS15203 improved mechanical allodynia caused by CIPN and reduced thermal hypersensitivity caused by CFA‐induced inflammatory pain. The reduction of chronic pain duration was observed only in male mice, but not in female mice, indicating a sex‐dependent effect at this particular dose of GPR171 agonist. Analysis of GPR171 protein levels in the midbrain Periaqueductal Gray showed that neuropathic pain decreased GPR171 receptor levels in males, but treatment by MS15203 rescued this decrease. Taken together, our findings show that GPR171 activity exhibits sexual dimorphism and can regulate multiple modalities of chronic pain.
