title: Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal.
abstract: Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not markedly altered by concurrent treatment with THC. Thus, THC can enhance some (antinociception, tolerance) but not all (dependence) effects of morphine.
authors.affiliation: Departments of Pharmacology (L.R.G., C.P.F.) and Psychiatry (C.P.F.), University of Texas Health Science Center, San Antonio, Texas.
authors.forename: L R
authors.initials: LR
authors.lastname: Gerak
authors.affiliation: Departments of Pharmacology (L.R.G., C.P.F.) and Psychiatry (C.P.F.), University of Texas Health Science Center, San Antonio, Texas france@uthscsa.edu.
authors.forename: C P
authors.initials: CP
authors.lastname: France
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; 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; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004361:Drug Tolerance; D006339:Heart Rate / Q000187:drug effects; D008253:Macaca mulatta; D009020:Morphine / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol