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

Vanessa Minervini, Sujata Dahal, Charles P. France

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)280-287
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume360
Issue number2
DOIs
StatePublished - Feb 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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