Behavioral characterization of κ opioid receptor agonist spiradoline and cannabinoid receptor agonist CP55940 mixtures in rats

Pain is a significant clinical problem, and there is a need for more effective treatmentswith reduced adverse effects that currently limit the use of m opioid receptor agonists. Synthetic κ opioid receptor agonists have no abuse liability and well-documented antinociceptive effects; however, adverse effects (diuresis, dysphoria) preclude their use in the clinic. Combining κ opioids with nonopioid drugs (cannabinoid receptor agonists) allows for smaller doses of each drug to produce antinociception. This study tested whether a potentially useful effect of the κ opioid receptor agonist 2-(3, 4- dichlorophenyl)-N-methyl-N-[(5R, 7S, 8S)-7-pyrrolidin-1-yl-1-oxaspiro[ 4.5]decan-8-yl] (spiradoline; antinociception) is selectively enhanced by the cannabinoid receptor agonist 2-[(1R, 2R, 5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)-phenol (CP55940). Cumulative dose-response functions were determined in eight male Sprague-Dawley rats for spiradoline (0.032-32.0 mg/kg, i.p.) and CP55940 (0.0032-1.0 mg/kg, i.p.) for antinociception, hypothermia, food-maintained responding, and diuresis. Alone, each drug dose dependently increased tail withdrawal latencies from 50°C water, decreased body temperature by ∼4°C, and eliminated food-maintained responding. Spiradoline, but not CP55940, significantly increased urine output at doses that eliminated responding. Smaller doses of spiradoline and CP55940 in mixtures (3:1, 1:1, and 1:3 spiradoline:CP55940) had effects comparable to those observed with larger doses of either drug administered alone: the interaction was additive for antinociception and additive or greater than additive for hypothermia and food-maintained responding. Collectively, these data fail to provide support for the use of these mixtures for treating acute pain; however, κ opioid/cannabinoidmixtures might be useful for treating pain under other conditions (e.g., chronic pain), but only if the adverse effects of both drugs are not enhanced in mixtures.