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

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. Kappa:mu 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 1:10, 1:3, 1:1, and 3:1 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 1:10 and 1:3 spiradoline:morphine mixtures and for 1:10, 1:3, and 1:1 spiradoline:etorphine mixtures. The potency of spiradoline to produce hypothermia was greater with 1:3 and 3:1 spiradoline:etorphine mixtures but not with 1:10 or 1:1 mixtures or with any spiradoline:morphine mixture. The effects of 1:3 spiradoline:morphine on responding for food were additive, whereas 1:1 and 3:1 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 kappa:mu mixtures might be advantageous to mu opioids alone.