Vol. 303, Issue 1, 340-346, October 2002

Decrease in Efficacy and Potency of Nonsteroidal Anti-Inflammatory Drugs by Chronic ⁹-Tetrahydrocannabinol Administration

Rene Anikwue, John W. Huffman, Zachary L. Martin and Sandra P. Welch

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia (R.A., Z.L.M., S.P.W.); and Department of Chemistry, Clemson University, Clemson, South Carolina (J.W.H.)

Cannabinoids have been shown to increase the release of arachadonic acid, whereas nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease the analgesic effects of cannabinoids. We evaluated the antinociceptive effects of chronic administration of ⁹-tetrahydrocannabinol (⁹-THC), anandamide (an endogenous cannabinoid), arachadonic acid, ethanolamine, and methanandamide on several NSAIDs via p.o. and/or i.p. routes of administration using the mouse p-phenylquinone (PPQ) test, a test for visceral nociception. Our studies with a cannabinoid receptor (CB1) antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A)], a CB2 antagonist [N-((1S)-endo-1,3,3-trimethyl-bicyclo-heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) (SR144528)], and an another CB2 agonist [1,1-dimethylbutyl-1-deoxy-⁹-THC (JWH-133)] were performed to better characterize PPQ interactions with cannabinoid receptors. The acute affects of ⁹-THC were blocked by SR141716A (i.p.) and partially blocked by SR144528 (i.p.). When NSAIDs (p.o.) were administered, the ED₅₀ values were as follows: 23 mg/kg aspirin, 3 mg/kg indomethacin, 5 mg/kg celecoxib, 3 mg/kg ketorolac, 57 mg/kg acetaminophen (32.3-99.8), and 0.8 mg/kg diclofenac (0.1-4.9). In animals given chronic ⁹-THC, only diclofenac and acetaminophen were active. Conversely, chronic methanandamide (i.p.) did not alter the antinociceptive effects of the NSAIDs. Neither the CB1 or CB2 antagonist blocked the effects of the NSAIDs. The effects of chronic arachadonic acid, ethanolamine, and anandamide could not be evaluated. In summary, our data indicate that chronic ⁹-THC alters the cyclooxygenase system. Alternatively, the data suggest that this alteration is not due to chronic endogenous cannabinoid release. Based upon these data, we hypothesize that human subjects who are chronic users of ⁹-THC may not respond to analgesic treatment with the above NSAIDs.