Pain is a significant clinical problem, and there is a need for more effective treatments with reduced adverse effects that currently limit the use of μ 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/cannabinoid mixtures 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.
- Received June 3, 2016.
- Accepted November 29, 2016.
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants K05DA017918 and T32DA031115] and the Welch Foundation [Grant AQ-0039].
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Portions of this manuscript were presented at the 2016 annual meetings Experimental Biology and American Society for Pharmacology and Experimental Therapeutics in San Diego, CA, and Behavior, Biology, and Chemistry: Translational Research in Addiction in San Antonio, TX. Minervini V and France CP, Behavioral characterization of spiradoline and CP55940 in rats: potential of drug mixtures for treating pain. EB2016 (poster). Sujata D, Minervini V, and France CP, Additive effects of spiradoline and CP55940 in rats: potential of drug mixtures for treating pain. Behavior, Biology and Chemistry: Translational Research in Addiction 2016 (poster).
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