Interactions between kappa and mu opioid receptor agonists: effects of the ratio of drugs in mixtures.

ABSTRACT

RATIONALE Pain is the leading reason for seeking health care, and mu opioid receptor agonists continue to be prescribed despite well-documented adverse effects. Kappa opioid receptor agonists have antinociceptive effects with little to no abuse liability and might be useful for treating pain in mixtures. Kappamu opioid mixtures might be useful if therapeutic effects of each drug can be selectively increased while reducing or avoiding the adverse effects that occur with larger doses of each drug alone. OBJECTIVE: This study characterized the effects of the kappa opioid receptor agonist spiradoline alone (0.32-56 mg/kg) and in 110, 13, 11, and 31 mixtures with the mu opioid receptor agonists morphine (1.0-32 mg/kg) and etorphine (1-10 µg/kg) on warm water tail-withdrawal latency, body temperature, responding for food, and fecal output in male Sprague-Dawley rats (n = 24). RESULTS: Antinociceptive effects were greater than additive for 110 and 13 spiradolinemorphine mixtures and for 110, 13, and 11 spiradolineetorphine mixtures. The potency of spiradoline to produce hypothermia was greater with 13 and 31 spiradolineetorphine mixtures but not with 110 or 11 mixtures or with any spiradolinemorphine mixture. The effects of 13 spiradolinemorphine on responding for food were additive, whereas 11 and 31 were greater than additive. Spiradoline did not significantly alter morphine-induced decreases in fecal output. CONCLUSIONS: Overall, mixtures of kappa and mu opioids might have therapeutic potential for treating pain, particularly when the mixture has a greater ratio of mu to kappa agonist. If adverse effects of each constituent drug are reduced or avoided, then kappamu mixtures might be advantageous to mu opioids alone.