Marijuana is a widely abused recreational drug well known for its psychoactive properties. Cannabinoids, the active ingredients of marijuana, elicit their neurobehavioral effects by interacting with the CB1 cannabinoid receptor subtype, expressed primarily in the brain but also present in some peripheral tissues. A second receptor subtype, the CB2 receptor, is expressed on cells of the immune system and is thought to be responsible for the immunosuppressant effects of cannabinoids. Recently, endogenous lipidlike substances have been identified, including arachidonyl ethanolamide (anandamide) and 2-arachidonyl glyceride, that bind to cannabinoid receptors and mimic many of the neurobehavioral effects of plant-derived cannabinoids. Both plant-derived cannabinoids and the endogenous ligands have been shown to elicit hypotension and bradycardia via activation of peripherally located CB1 receptors. Possible underlying mechanisms include presynaptic CB1 receptor mediated inhibition of norepinephrine release from peripheral sympathetic nerve terminals, and/or direct vasodilation via activation of vascular cannabinoid receptors. The latter may also be the target of endocannabinoids of vascular endothelial origin. Recent studies indicate that a peripheral endogenous cannabinoid system in circulating macrophages and platelets is activated in hemorrhagic and septic shock and may contribute to the hypotension associated with these conditions via activation of vascular cannabinoid receptors. The potential role of this mechanism in human shock conditions is under investigation.

Animals↗

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The discovery of endogenous cannabinoids.

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Animals↗

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The tachycardia associated with the defense reaction involves activation of both GABAA and GABAB receptors in the nucleus tractus solitarii.

In urethane-anesthetized rats, the tachycardia associated with the defense reaction can be elicited by unilateral microinjections of the GABAA-antagonist, bicuculline methyliodide (BMI, 20 pmol), into the dorsomedial nucleus (DMN) of the hypothalamus. This effect is thought to be mediated via a pathway that activates GABAergic interneurons in the medullary nucleus tractus solitarii (NTS) which, in turn, inhibit vagal outflow to the heart. Ipsilateral intra-NTS microinjection of BMI (10 pmol) or the GABAB-antagonist, 2-OH-saclofen (400 pmol), attenuated the tachycardia elicited from the DMN. The tachycardia was also inhibited by intra-NTS administration of the NMDA-receptor channel blocker, MK-801 (30 pmol), or the non-NMDA antagonist, CNQX (400 pmol). These findings are interpreted to indicate that a) GABAergic control of heart rate at the level of the NTS is mediated by both GABAA and GABAB receptors, and b) descending input from the DMN to the NTS releases GABA via glutamate acting on ionotropic glutamate receptors located on GABAergic interneurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗