Acute Δ(9)-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice

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 Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, have yet to be investigated. Male C57BL/6J mice were fasted, administered vehicle or Δ(9)-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 Δ(9)-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. Δ(9)-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). Δ(9)-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. Δ(9)-THC between each behavior measure was 7-18. These data indicate that the phytocannabinoid Δ(9)-THC protects against diclofenac-induced gastric inflammatory tissue damage at doses insufficient to cause common cannabinoid side effects.

Keywords: Cannabinoid; Cyclooxygenase; Diclofenac; Gastric inflammation; NSAID dyspepsia; Tetrahydrocannabinol.

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.

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.

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.