GPR171 Agonist, MS15203, Effectively Enhances Morphine Antinociception Without Modulating Detrimental Side Effects

Abstract

Opioid drugs are limited in clinical effectiveness because of their propensity for tolerance, addiction, withdrawal, and respiratory depression. Nonetheless, this drug class is still readily prescribed for acute and chronic pain, often to the long-term detriment of patients. Safer pain therapeutics are desperately needed. One novel avenue of drug development is to search for a target capable of enhancing opioid antinociception without enhancing negative side effects. This would allow for increased opioid effectiveness with lower doses, thus minimizing negative side effects and postponing dose escalation. The previous orphan receptor, GPR171, is one such target. Our recent work showed that an agonist for GPR171, MS15203 enhances morphine antinociception in two rodent acute pain assays (McDermott et al., 2019). Combining these two drugs could potentially lead to greater antinociception with lower opioid doses. The next step in vetting MS15203 as a novel pain therapeutic is to determine its effect on negative opioid side effects. In this current study we utilized three rodent behavioral assays to assess MS15203 in tolerance development, opioid withdrawal, and reward liability. Additionally, we used immunohistochemistry to assess ex vivo MS15203-induced dopamine activation in the ventral tegmental area (VTA). Results from a hot plate dose-response show that MS15203 has no significant effect on morphine tolerance development in both males and females. However, MS15203 significantly decreases morphine tolerance in females on the tail flick test, suggesting a sex-specific and spinal-specific effect. Results from a naloxone precipitated withdrawal assay show that MS15203 does not significantly alter morphine withdrawal. Results from a conditioned place preference assay, show that MS15203 alone causes no significant place preference, and has no significant modulatory effect when paired with morphine. Similarly, MS15203, causes no significant VTA activation alone, and has no significant modulatory effect on morphine-induced activation. Taken together these results present GPR171 agonist MS15203 as an enhancer of morphine antinociception, and an overall neutral agent in morphine tolerance, withdrawal, and reward. Future studies should assess MS15203 on respiratory depression.