Assessing the synergistic effects of morphine and MP‐III‐024 co‐administration: enhanced antinociception with reduced side effects

Abstract

Opioid analgesics are critical for acute and chronic pain management, but important side effects—including tolerance, constipation, respiratory depression, and abuse liability—limit their safety and utility. To provide patients with safer analgesic options, it is critically important to identify of new pharmacotherapeutic strategies to treat pain. Activation of µ‐opioid receptors (MORs) in central and peripheral nociceptive pathways mediates opioid analgesia and their critical side effects. Antinociception can also be achieved via selective enhancement of GABAergic signaling at ionotropic GABAA receptors. α2 and α3 subunit‐containing GABAA receptors (α2/α3GABAA), which are co‐expressed with MORs in dorsal horn spinal pathways important to nociceptive transmission, can be selectively targeted with novel imidazodiazepine positive allosteric modulators (PAMs), such as MP‐III‐024, which produces antinociceptive effects with limited behavioral disruption. MP‐III‐024 co‐administered with morphine produces synergistic antinociceptive and anti‐hyperalgesic effects. In this study, we evaluated whether MP‐III‐024/morphine co‐administration produces sub‐additive or synergistic effects in behavioral tests sensitive to morphine side effects. Herein we report that co‐administration of MP‐III‐024/morphine at a 0.94/1 ratio (synergistic in models of antinociception) produced sub‐additive effects in morphine‐induced hyperlocomotion and in measures of behavioral disruption in food‐maintained operant responding. Ongoing studies are evaluating the effects of MP‐III‐024/morphine co‐administration on tolerance in the hot plate test and in conditioned place preference. These experiments are the first comprehensive preclinical analyses of a dual MOR‐α2/α3GABAA pharmacotherapy strategy which may increase the therapeutic window between desirable opioid analgesic effects and side effects.