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Decrease in Efficacy and Potency of Nonsteroidal Anti-Inflammatory Drugs
by Chronic Δ9-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.). Address correspondence to: Dr. Sandra P. Welch, Department of
Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth
University, Richmond, Virginia. E-mail: swelch@hsc.vcu.edu
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 Δ9-tetrahydrocannabinol
(Δ9-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-Δ9-THC
(JWH-133)] were performed to better characterize PPQ interactions with
cannabinoid receptors.
The acute affects of Δ9-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 Δ9-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 Δ9-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 Δ9-THC
may not respond to analgesic treatment with the above NSAIDs.
Copyright © 2002 by
The American Society for Pharmacology and Experimental Therapeutics
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