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. 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.

Keywords: Antinociception; Drug interactions; Drug mixtures; Opioids; Rats.

Figure 1

Tail withdrawal latencies from 50°C water (A) and rectal body temperature (B) after the administration of spiradoline, morphine, or etorphine and operant (lever press) responding for food (C) after the administration of spiradoline or morphine. Ordinates: mean (±1 SEM) latency in seconds (upper), mean (±1 SEM) body temperature in °C (middle), and mean (±1 SEM) response rate in responses per second (lower). Abscissae: cumulative dose in mg/kg (spiradoline and morphine) or μg/kg (etorphine) body weight. The same group of 7 rats contributed to the antinociception and body temperature study and a different group of 7 rats contributed to the operant study.

Figure 2

Antinociceptive effects (A) and body temperature (B) for spiradoline administered alone (open symbols with dashed line; note that the same data are plotted in the left and right panels) and in mixtures with morphine (left) or etorphine (right) in 1:10, 1:3, 1:1, and 3:1 ratios and response rate for food (C) for spiradoline administered alone and in mixtures with morphine. Ordinates: mean (±1 SEM) % Maximum Possible Effect (upper), mean (±1 SEM) change in body temperature from saline control in °C (middle), and mean (±1 SEM) percent of the saline control rate (lower). Abscissae: cumulative spiradoline dose in mg/kg body weight. The same group of 7 rats contributed to antinociception and body temperature study and a different group of 7 rats contributed to the operant study.

Figure 3

Linear regressions fit to the predicted additive effects and observed (empirically determined) effects for the antinociceptive effects for spiradoline:morphine mixtures (A), antinociceptive effects for spiradoline:etorphine mixtures (B), and food-maintained responding for spiradoline:morphine mixtures (C). Ordinates: mean (±1 SEM) % Maximum Possible Effect (upper and middle) and mean (±1 SEM) percent of the saline control rate (lower). Abscissae: cumulative spiradoline equivalent dose in mg/kg body weight. The same group of 7 rats contributed to the antinociception study and a different group of 7 rats contributed to the operant study.

Figure 4

Linear regressions fit to morphine and spiradoline:morphine mixtures for antinociception (A) and to morphine for fecal output (B). Shaded region denotes the 95% CI for antinociception (upper) and fecal output (lower). Ordinates: mean (±1 SEM) % Maximum Possible Effect (upper) and mean (±1 SEM) percent of the saline control fecal output (lower). Abscissae: morphine equivalent dose in mg/kg body weight. A group of 7 rats contributed to the antinociception study and a different group of 8 rats contributed to the fecal output study.