Antinociceptive effects of mixtures of mu opioid receptor agonists and cannabinoid receptor agonists in rats: Impact of drug and fixed-dose ratio

Abstract

Pain is a significant clinical problem, and there is a need for effective pharmacotherapies with fewer adverse effects than currently available drugs (e.g., mu opioid receptor agonists). Cannabinoid receptor agonists enhance the antinociceptive effects of mu opioid receptor agonists, but it remains unclear which drugs and in what proportion will yield the most effective and safest treatments. The antinociceptive effects of the mu opioid receptor agonists etorphine and morphine alone and in combination with the cannabinoid receptor agonists Δ⁹-THC and CP55940 were studied in male Sprague-Dawley rats (n = 16) using a warm water tail withdrawal procedure. The ratio of opioid to cannabinoid (3:1, 1:1, and 1:3) varied for each mixture. Drugs administered alone or as pairwise mixtures of an opioid and a cannabinoid dose-dependently increased tail withdrawal latency. Mixtures with morphine produced supra-additive (CP55940) and additive (Δ⁹-THC) effects, whereas mixtures with etorphine and either cannabinoid were sub-additive. The interactions were not different among ratios for a particular mixture. The nature of the interaction between opioids and cannabinoids with regard to antinociceptive effects varies with the particular drugs in the mixture, which can have implications for designing combination therapies for pain.

Keywords: Antinociception; Cannabinoid receptor agonist; Drug-drug interactions; Rats; Thermal nociception; mu opioid receptor agonist.

Fig. 1

Antinociceptive effects of cumulative doses of etorphine (squares), morphine (circles), CP55940 (triangles, left panel), and Δ⁹-THC (triangles, right panel) alone with 50°C water with an inter-injection interval of 30 min. Data in the left panel were collected in one group of 8 rats whereas data in the right panel were collected in another group of 8 rats. Each curve represents the average of two determinations. Abscissae: dose in milligrams per kilogram body weight. Ordinate: percentage of the maximum possible effect (MPE; mean ± 1 standard error of the mean).

Fig. 2

Antinociceptive effects of cumulative doses of etorphine (open squares) or morphine alone (open symbols) and in combination (filled symbols) with CP55940 or Δ⁹-THC with 50°C water. The ratio of opioid to cannabinoid in the mixture, 3:1 (upright triangles), 1:1 (circles), and 1:3 (inverted triangles), varied across tests. Data in the two leftmost panels were collected in one group of 8 rats whereas data in the two rightmost panels were collected in another group of 8 rats. Abscissae: dose of the opioid administered alone or as part of a mixture in milligrams per kilogram body weight. Ordinate: percentage of the maximum possible effect (MPE; mean ± 1 standard error of the mean).

Fig. 3

Comparison of the predicted effects of the drug mixtures based on the assumption of an additive interaction (open symbols) with the observed effects (filled symbols) for each dose ratio and each dose pair. Abscissae: additive, opioid-equivalent total dose in milligrams per kilogram body weight; horizontal error bars indicate the standard error of the mean for the opioid-equivalent dose (see Data Analyses for details). Ordinate: percentage of the maximum possible effect (MPE; mean ± 1 standard error of the mean).