The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jun 1997
Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors.
Previous studies indicate that the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR141716A), inhibits the anandamide- and delta9-tetrahydrocannabinol- (THC) induced hypotension and bradycardia in anesthetized rats with a potency similar to that observed for SR141716A antagonism of THC-induced neurobehavioral effects. To further test the role of CB1 receptors in the cardiovascular effects of cannabinoids, we examined two additional criteria for receptor-specific interactions: the rank order of potency of agonists and stereoselectivity. A series of cannabinoid analogs including the enantiomeric pair (-)-11-OH-delta9-THC dimethylheptyl (+)-11-OH-delta9-THC dimethylheptyl were evaluated for their effects on arterial blood pressure and heart rate in urethane anesthetized rats. ⋯ There was no hypotension or bradycardia after palmitoylethanolamine or (+)-11-OH-delta9-THC dimethylheptyl. An initial pressor response was also observed with THC and anandamide, which was not antagonized by SR141716A. We conclude that the similar rank orders of potency, stereoselectivity and sensitivity to blockade by SR141716A indicate the involvement of CB1-like receptors in the hypotensive and bradycardic actions of cannabinoids, whereas the mechanism of the pressor effect of THC and anandamide remains unclear.
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J. Pharmacol. Exp. Ther. · Jun 1997
Spinal infusion of N-methyl-D-aspartate antagonist MK801 induces hypersensitivity to the spinal alpha-2 agonist ST91 in the rat.
MK801 (MK), an N-methyl-D-aspartate (NMDA) receptor antagonist, attenuates tolerance to spinal opioids. Whether this applies to other G-protein-coupled receptor systems is unknown. This study examines the effects of continuous spinal MK on tolerance to the antinociceptive effect of continuous spinal infusion of the alpha-2 agonist ST91 (ST). ⋯ In conclusion, chronic spinal MK partially attenuates loss of sensitivity to chronic spinal ST. This supports the hypothesis that opioid- and adrenoceptor-induced tolerances are similarly modulated by the NMDA receptor. However, the increased sensitivity induced by MK alone suggests that NMDA receptor antagonism may not prevent the development of tolerance itself but may alter the expression of tolerance by inducing sensitivity via other alterations in cellular function.