Combination drug therapy to treat pain with minimal or no abuse potential and side-effects - PROJECT SUMMARY/ABSTRACT Opioid analgesics are critical for acute and chronic pain management, but important side effects limit their safety and utility, including tolerance, constipation, respiratory depression, and abuse liability. We have determined that simultaneous activation of µ-opioid receptors (MORs), with the opioid analgesic morphine, and enhancement of GABAergic signaling at α2 and α3 subunit-containing GABAA (α2/α3GABAA) receptors, with the novel imidazodiazepine ligand MP-III-024, produces synergistic antinociceptive and anti-hyperalgesic effects. Preliminary data also indicate that MP-III-024/morphine mixes produce sub-additive effects in behavioral tests sensitive to morphine side effects, supporting further investigation of a dual pharmacological approach that simultaneously targets MOR and α2/α3GABAA to enhance analgesic effects without increasing side effects. We hypothesize that this dual pharmacology approach will result in more effective antinociception with reduced development of critical opioid side effects. To test this hypothesis, we will perform a comprehensive preclinical analysis of the effects of dual MOR-α2/α3GABAA pharmacotherapy in models of pain, tolerance, constipation, respiratory depression, and abuse liability. We will systematically test whether κ-opioid receptors or δ-opioid receptors also contribute to the antinociceptive effects of MP-III-024/morphine mixtures. Finally, we will determine whether bivalent ligands designed to simultaneously target MOR and α2/α3GABAA will produce analgesic effects and represent a new line of medication development. If successful, these studies would identify a new method to enhance opioid analgesia, requiring lower necessary doses of opioid medications, in turn reducing the likelihood of dangerous side effects or the development of opioid dependence and addiction.
