Acute Δ9-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice.

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Acute Δ9-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice.

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Department of Psychology, West Virginia University, Morgantown, WV USA. Electronic address: sgkinsey@mail.wvu.edu.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs), which are among the most widely used analgesics in the world, cause gastrointestinal inflammation that is potentially life-threatening. Although inhibitors of endocannabinoid catabolic enzymes protect against gastropathy in fasted NSAID-treated mice, the gastroprotective effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, have yet to be investigated. Male C57BL/6J mice were fasted, administered vehicle or Δ9-THC (.01-50mg/kg; oral or intraperitoneal), and then treated with the NSAID diclofenac sodium (100mg/kg, p.o.) to induce gastric lesions. In separate groups of mice, the cannabimimetic behavioral effects of Δ9-THC given via each route of administration were compared using a battery of tests, consisting of assessment of locomotor activity, nociception in the tail withdrawal test, catalepsy in the bar test, and hypothermia. Δ9-THC dose-dependently attenuated diclofenac-induced gastric hemorrhagic streaks through both p.o. and i.p. routes of administration (ED50 (95% confidence interval)=0.64 (0.26-1.55) mg/kg and 0.06 (0.01-0.34) mg/kg, respectively). Δ9-THC given i.p. was 2-3 orders of magnitude more potent in reducing diclofenac-induced gastric ulcers than in producing locomotor immobility, antinociception, hypothermia, and catalepsy, while the potency of ratio of p.o. Δ9-THC between each behavior measure was 7-18. These data indicate that the phytocannabinoid Δ9-THC protects against diclofenac-induced gastric inflammatory tissue damage at doses insufficient to cause common cannabinoid side effects.

Copyright © 2013. Published by Elsevier B.V.

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 23769745

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Figures and tables from this article:

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Fig. 1. THC dose-dependently attenuates diclofenac-induced gastric hemorrhages. THC was administered intraperitoneally (i.p.) or orally (p.o.) 1 h before diclofenac sodium (100 mg/kg, p.o.) was administered in fasted mice. Data presented as mean±S.E.M. (n=7–8). Open circles: intraperitoneal Δ9-THC; closed circles: oral Δ9-THC.*P<0.05,**P<0.01 vs. vehicle pretreatment. All mice were treated with diclofenac.

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Fig. 2. Representative images of mouse stomachs. Vehicle or Δ9-THC (1 mg/kg, i.p. or 5 mg/kg, p.o.) was administered 1 h before diclofenac sodium (100 mg/kg, p.o.) was administered in fasted mice. Yellow arrows indicate hemorrhagic streaks. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Fig. 3. Dose-response curves of Δ9-THC sensitive behaviors. Δ9-THC was administered (i.p. or p.o.), and then assessed 1 h later in a battery of tests highly sensitive to the pharmacological effects of cannabinoids, including (A) spontaneous locomotor activity (B) catalepsy, (C) analgesia in the tail immersion test, and (D) hypothermia. Data presented as mean±S.E.M. (n=8–12). Open circles: intraperitoneal Δ9-THC; closed circles: oral Δ9-THC. *P<0.05,**P<0.01 vs. vehicle.

Table 1. ED50 (95% confidence limit) values and potency ratios (95% C.L.) of Δ9-THC (mg/kg) in blocking diclofenac-induced gastric hemorrhages and in the tetrad cannabinoid test battery. Mice were treated with Δ9-THC and were either treated with diclofenac to induce gastric hemorrhages or were screened in a cannabinoid sensitive test battery.

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