THERAPEUTIC POTENTIAL OF KAPPA OPIOID/CANNABINOID MIXTURES FOR TREATING PAIN

Prescription opioids (mu opioid receptor agonists) are the drugs of choice for treating moderate to severe pain,despite well-documented adverse effects of those drugs (e.g., abuse, respiratory depression) and significantpublic health concerns. Mu opioids are the most widely abused of all prescription medications and fataloverdoses have reached epidemic levels. Thus, there is a dire need for more effective treatments for pain withfewer deleterious effects. Kappa opioid receptor agonists do not produce respiratory depression and are notlikely to be abused; however, clinical use of kappa opioids has been precluded by adverse effects in humans,such as dysphoria, hallucinations, and diuresis. If these centrally mediated adverse effects can be avoided, thenkappa opioids might be promising targets for treating pain and would be preferred to mu opioids that have a highrisk of abuse and overdose. Our laboratory showed that by combining a kappa opioid with a non-opioid drug thatalso produces antinociception (e.g., a cannabinoid receptor agonist), smaller doses of each drug in a the mixtureproduce antinociceptive effects in an additive manner. If adverse effects are not apparent at smaller doses, thenkappa opioids in combination with cannabinoids could have therapeutic potential for treating pain. Thetherapeutic potential of kappa opioid/cannabinoid mixtures is perhaps greatest for treating chronic inflammatorypain over other types of pain. The proposed studies will test the hypothesis that a kappa opioid/cannabinoidmixture further enhances antinociceptive but not adverse effects in rats with chronic inflammation due toincreased function at kappa and cannabinoid receptors that mediate antinociception peripherally and spinally.Aim 1 characterizes the antinociceptive effects of a kappa opioid/cannabinoid mixture to test the hypothesis thatsmaller doses of drugs in a mixture have antinociceptive effects that are greater than additive. Aim 2 usesoperant choice procedures to quantify adverse effects of a kappa opioid/cannabinoid mixture to test thehypothesis that the potency of a mixture is decreased in rats with inflammation. Aim 3 compares kappa opioidand cannabinoid receptor function from rats with and without inflammation. These studies explore a novel andinnovative approach (kappa opioid/cannabinoid mixture) for treating pain without the risk of abuse that currentlylimits the clinical use of mu opioids. Additionally, this grant will support a postdoctoral training plan for theapplicant to develop a unique research trajectory and transition to a career as an independent investigator.