Additive antinociceptive effects of mixtures of the κ-opioid receptor agonist spiradoline and the cannabinoid receptor agonist CP55940 in rats

Abstract

Pain is a significant clinical problem, and there is a need for pharmacotherapies that are more effective with fewer adverse effects than currently available medications. Cannabinoid receptor agonists enhance the antinociceptive effects of μ-opioid receptor agonists; it is unclear whether they impact the effects of agonists acting at other opioid receptors. κ-Opioid receptor agonists have antinociceptive effects, but their clinical use is precluded by adverse effects; however, their therapeutic potential might be realized if antinociceptive effects could be selectively enhanced. In this study, the antinociceptive effects of the cannabinoid receptor agonist CP55940 and the κ-opioid receptor agonist spiradoline, alone and in combination, were studied in rats (n=7) using a warm water tail-withdrawal procedure. When administered alone, CP55940 (0.032-1.0 mg/kg) and spiradoline (1.0-32.0 mg/kg) increased tail-withdrawal latency, and mixtures of CP55940 and spiradoline (ratios of 1 : 3, 1 : 1, and 3 : 1) produced additive effects. It remains to be determined whether this additive interaction between a κ-opioid receptor agonist and a cannabinoid receptor agonist is selective for antinociception and whether it can be generalized to other drugs.

Figure 1

(A) Antinociceptive effects of cumulative doses of CP55940 and spiradoline alone (open symbols) and in combination (filled symbols) with 50°C water in rats (n = 7) with an inter-injection interval of 30 minutes. The ratio of CP55940 to spiradoline in the mixture, 1:3 (diamonds), 1:1 (squares), and 3:1 (inverted triangles), varied across tests. Abscissae: dose in milligrams per kilogram body weight. Ordinate: % maximum possible effect (MPE) ± 1 SEM (see “Data Analyses” for details). (B) Isobologram for mixtures of CP55940 and spiradoline (same data presented in A). Open symbols indicate the ED₅₀ valued for CP55940 alone (triangle) and spiradoline alone (circle); the solid line connecting the open symbols indicates the line of additivity. Filled symbols indicate the ED₅₀ values for mixtures of CP55940 and spiradoline (same ratios and symbols presented in A). Abscissae: ED₅₀ for spiradoline in milligrams per kilogram body weight (± 95% confidence interval). Ordinate: ED₅₀ for CP55940 in milligrams per kilogram body weight (± 95% confidence interval). (C) Comparisons of the predicted effects of the drug mixtures based on the assumption of an additive interaction (open symbols) to the observed effects (filled symbols) for each dose ratio. Abscissae: additive total dose (in spiradoline-equivalent doses) in milligrams per kilogram body weight (see “Data Analyses” for details). Ordinate: % MPE (± 1 SEM).