title: Interactions between μ-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration.
abstract: Cannabinoid receptor agonists enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combinations of these drugs might enhance therapeutic effectiveness (e.g., analgesia). However, it is not clear whether combinations of these drugs also enhance abuse or dependence liability. This experiment examined whether combinations of cannabinoids and opioids that enhance antinociception also increase abuse-related effects by studying the effects of the cannabinoid receptor agonists 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212) on the antinociceptive, discriminative stimulus, and positive reinforcing effects of μ-opioid receptor agonists in rhesus monkeys. In one group of monkeys (n = 3), morphine (0.1-5.6 mg/kg s.c.), CP 55,940 (0.0032-0.032 mg/kg s.c.), and WIN 55,212 (0.1-1.0 mg/kg s.c.) dose-dependently increased tail withdrawal latency from 50°C water, and pretreatment with small, otherwise ineffective, doses of CP 55,940 and WIN 55,212 shifted the morphine dose-effect curve to the left. In monkeys (n = 3) discriminating 3.2 mg/kg morphine, CP 55,940 (0.01-0.032 mg/kg s.c.) and WIN 55,212 (0.1-1.78 mg/kg s.c.) attenuated the discriminative stimulus effects of morphine, shifting the dose-effect curve to the right. In monkeys (n = 4) self-administering heroin (0.32-32.0 µg/kg/infusion i.v.), CP 55,940 (0.001-0.032 mg/kg s.c.), and WIN 55,212 (0.1-1.0 mg/kg s.c.) shifted the heroin dose-effect curve rightward and downward. Cannabinoid receptor agonists CP 55,940 and WIN 55,212 enhanced the antinociceptive effects but not the discriminative stimulus or positive reinforcing effects of μ-opioid receptor agonists in rhesus monkeys, supporting the view that combining cannabinoid and opioid receptor agonists might result in enhanced treatment effectiveness for pain without similarly enhancing abuse and dependence liability.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Maguire
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Yang
authors.forename: Charles P
authors.initials: CP
authors.lastname: France
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D003511:Cyclohexanols / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D006556:Heroin Dependence / Q000523:psychology; D006358:Hot Temperature; D008253:Macaca mulatta; D009020:Morphine / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012646:Self Administration
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D017450:Receptors, Opioid, mu; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D009020:Morphine; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
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