The Neuropeptide Receptor System, BigLEN‐GPR171, Interacts with the Opioid System to Relieve Pain

Abstract

ProSAAS derived peptides, such as BigLEN, are abundantly expressed throughout the brain. We recently identified BigLEN as the endogenous peptide for the orphan receptor GPR171. Immunohistochemical analysis shows that both BigLEN and GPR171 are highly expressed in areas of the brain involved in pain modulation, including the periaqueductal gray (PAG). In addition, we find that GPR171 is co‐localized with mu opioid receptors (MOPr) in the ventrolateral PAG. Also, using immunohistochemistry we have identified that GPR171 is expressed in a portion of vGLut2 and GAD67 positive neurons. This brain region is especially known to contribute to opioid antinociception and tolerance. Given the expression pattern of GPR171, we hypothesized that GPR171 contributes to antinociception and tolerance. To test this, mice were injected with a GPR171 antagonist (MS21570; 5 mg/kg, i.p.) followed by the tail flick pain test which produced an increase in antinociception compared to controls. However, this compound is not as efficacious as morphine and pretreatment with MS21570 10 min prior to morphine (10 mg/kg, s.c.) did not alter morphine‐induced antinociception. To assess the role of GPR171 in morphine tolerance, mice were injected with morphine twice daily for 5 days. A subset of mice were pretreated with MS21570 10 min prior to each morphine injection. Those mice pretreated with MS21570 showed a decrease in the development of morphine tolerance. To understand how these systems may be working together, GPR171 was knocked down in Neuro2A cells which led to a decrease in MOPr‐mediated GTPγS signaling by DAMGO, but had no effect on GTPγS signaling by the delta opioid receptor agonist, deltorphin. This data suggests that the MOPr agonist, DAMGO, requires GPR171 expression in order to signal despite not directly binding to GPR171. Studies investigating GPR171 expression and signaling changes within the PAG following chronic morphine are ongoing. Taken together, this data shows that GPR171 and MOPr interact with one another and GPR171 antagonist may be a novel target to treat pain or opioid tolerance.Support or Funding InformationSupported by NIH grants, DA019521 and NS026880 (to LAD) and NIDA postdoctoral training grant DA007135 and a Young Investigator Grant from the Brain and Behavior Research Foundation (to ENB).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.