title: Behavioral Characterization of κ Opioid Receptor Agonist Spiradoline and Cannabinoid Receptor Agonist CP55940 Mixtures in Rats.
abstract: 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.
authors.affiliation: Departments of Pharmacology (V.M., S.D., C.P.F.) and Psychiatry (C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Minervini
authors.affiliation: Departments of Pharmacology (V.M., S.D., C.P.F.) and Psychiatry (C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Sujata
authors.initials: S
authors.lastname: Dahal
authors.affiliation: Departments of Pharmacology (V.M., S.D., C.P.F.) and Psychiatry (C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas france@uthsca.edu.
authors.forename: Charles P
authors.initials: CP
authors.lastname: France
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D003511:Cyclohexanols / Q000494:pharmacology*; D004357:Drug Synergism; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: D063386:Cannabinoid Receptor Agonists; D003511:Cyclohexanols; D011759:Pyrrolidines; D043882:Receptors, Cannabinoid; D017473:Receptors, Opioid, kappa; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C051272:spiradoline