Interactions between Mu and Kappa Opioid Receptor Agonists: Antinociceptive and Adverse Effects in Rats

Prescription opioids (mu opioid receptor agonists) are commonly used to treat moderate to severe pain despite their well‐documented adverse effects (e.g., constipation, abuse). Kappa opioid receptor agonists also have antinociceptive effects and adverse effects, including dysphoria and diuresis that preclude their use in the clinic. Kappa opioid receptor agonists are not likely to be abused, and they might be useful for treating pain in a drug mixture. A mu/kappa opioid mixture might reduce the dose of each drug needed to produce therapeutic (antinociceptive) effects and avoid the adverse effects that occur with larger doses of each drug alone. Additive antinociceptive effects have been reported for the mu/kappa opioid mixture sufentanil:U50488H. The current experiment compared antinociceptive, hypothermic, and rate‐decreasing effects of the kappa opioid receptor agonist spiradoline in combination with the mu opioid receptor agonists morphine or etorphine to test the hypothesis that a mu/kappa opioid mixture selectively enhances antinociceptive effects. All drugs were administered i.p. using a cumulative dosing procedure with 30‐min inter‐injection intervals. Dose‐effect functions were determined in 7 male Sprague Dawley rats for spiradoline (3.2 – 56.0 mg/kg), morphine (1.78 – 32.0 mg/kg), and etorphine (0.001 – 0.1 mg/kg) for latency to remove the tail from warm (40, 50, and 55°C) water and for rectal body temperature. In a separate group of 7 rats, dose‐effect functions were determined for spiradoline and morphine in decreasing responding for food. Given alone, spiradoline and morphine increased tail withdrawal latency from 50°C water to 20 s (maximum); etorphine increased tail withdrawal latency to 15 s. Spiradoline decreased body temperature by approximately 3°C, whereas morphine, but not etorphine, increased body temperature by approximately 1.5°C. Spiradoline alone and morphine alone decreased responding for food to <20% of baseline rates. ED 50 values were used to determine the doses for mixtures in ratios of 3:1, 1:1, and 1:3. Mixtures of spiradoline:morphine (3:1 and 1:1) and spiradoline:etorphine (1:1) produced additive antinociceptive effects, and spiradoline:morphine (1:3) produced greater than additive antinociceptive effects (ED 50 potency ratio of 1.9). Neither morphine nor etorphine altered the hypothermic effects of spiradoline. Morphine and etorphine enhanced a potentially useful effect (antinociception) as well as an adverse effect (hypothermia) of spiradoline. It remains to be determined whether mu/kappa mixtures also enhance other adverse effects (e.g., constipation, dysphoric effects) and whether enhancement depends on the particular drugs in the mixture. Mu/kappa opioid mixtures may have greater therapeutic potential than mu opioids alone for treating moderate to severe pain, but only if adverse effects of each drug are not enhanced. Support or Funding Information This work was supported by the National Institute on Drug Abuse grants K05DA017918 and T32DA031115, the Welch Foundation Grant AQ‐0039, and the ASPET Summer Undergraduate Research Fellowship program.