Effects of the cannabinoid receptor agonist CP 55,940 and the cannabinoid receptor antagonist SR 141716 on intracranial self-stimulation in Lewis rats

Cerebral vascular smooth muscle cells express the CB1 cannabinoid receptor, and CB1 receptor agonists produce vasodilation of cerebral arteries. The purpose of this study was to determine whether vasoconstriction of rat middle cerebral artery (MCA) results in the local formation of endocannabinoids (eCBs), which, via activation of CB1 receptors, oppose the vasoconstriction in a feedback manner. The thromboxane A2 (TXA2) mimetic U-46619 significantly increased N-arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG) content of isolated MCA, whereas 5-hydroxytrypamine (5-HT) decreased AEA and 2-AG content. If eCBs play a feedback role in the regulation of MCA tone, then CB1 receptor antagonists should enhance the constriction of MCA produced by U-46619 but not 5-HT. U-46619 caused concentration-dependent constrictions of endothelium-denuded MCA. Two CB1 receptor antagonists SR-141716 and AM-251 decreased the EC50 value for U-46619 to constrict endothelium-denuded MCA without affecting the maximal effect. A low concentration of CB1 receptor agonist Win-55212-2 (30 nM) produced vasodilation of MCAs constricted with low but not saturating concentrations of U-46619. SR-141716 had no effect on the 5-HT concentration-contraction relationship. These data suggest that TXA2 receptor activation increases MCA eCB content, which, via activation of CB1 receptors, reduces the constriction produced by moderate concentrations of the TXA2 agonist. Although 5-HT-induced vasoconstriction is reduced by exogenous CB1 receptor agonist, activation of 5-HT receptors does not increase eCB content. These results suggest that MCA production of eCBs is not regulated by constriction per se but likely via a signaling pathway that is specific for TXA2 receptors and not 5-HT receptors.

Download Full-text

Evidence for an Interaction between CB1 Cannabinoid and Melanocortin MCR-4 Receptors in Regulating Food Intake

Endocrinology ◽

10.1210/en.2004-0059 ◽

2004 ◽

Vol 145 (7) ◽

pp. 3224-3231 ◽

Cited By ~ 83

Author(s):

A. N. A. Verty ◽

J. R. McFarlane ◽

I. S. McGregor ◽

P. E. Mallet

Keyword(s):

Locomotor Activity ◽

Food Intake ◽

Receptor Antagonist ◽

Receptor Agonist ◽

Cannabinoid Receptors ◽

Cb1 Receptor ◽

Melanocortin Receptor ◽

Cb1 Receptors ◽

Melanocortin System ◽

Sr 141716

Abstract Melanocortin receptor 4 (MCR4) and CB1 cannabinoid receptors independently modulate food intake. Although an interaction between the cannabinoid and melanocortin systems has been found in recovery from hemorrhagic shock, the interaction between these systems in modulating food intake has not yet been examined. The present study had two primary purposes: 1) to examine whether the cannabinoid and melanocortin systems act independently or synergistically in suppressing food intake; and 2) to determine the relative position of the CB1 receptors in the chain of control of food intake in relation to the melanocortin system. Rats were habituated to the test environment and injection procedure and then received intracerebroventicular injections of various combinations of the MCR4 receptor antagonist JKC-363, the CB1 receptor agonist Δ9-tetrahydrocannabinol, the MCR4 receptor agonist α-MSH, or the cannabinoid CB1 receptor antagonist SR 141716. Food intake and locomotor activity were then recorded for 120 min. When administrated alone, SR 141716 and α-MSH dose-dependently attenuated baseline feeding, whereas sub-anorectic doses of SR 141716 and α-MSH synergistically attenuated baseline feeding when combined. Δ9-Tetrahydrocannabinol-induced feeding was not blocked by α-MSH, whereas SR 141716 dose-dependently attenuated JKC-363-induced feeding. Locomotor activity was not significantly affected by any drug treatment, suggesting that the observed effects on feeding were not due to a nonspecific reduction in motivated behavior. These findings revealed a synergistic interaction between the cannabinoid and melanocortin systems in feeding behavior. These results further suggested that CB1 receptors are located downstream from melanocortin receptors and CB1 receptor signaling is necessary to prevent the melanocortin system from altering food intake.

Download Full-text

Additive Interaction of the Cannabinoid Receptor I Agonist Arachidonyl-2-chloroethylamide with Etomidate in a Sedation Model in Mice

Anesthesiology ◽

10.1097/aln.0b013e318167aef7 ◽

2008 ◽

Vol 108 (4) ◽

pp. 669-674 ◽

Cited By ~ 5

Author(s):

Patrick Meybohm ◽

Philipp-Alexander Brand ◽

Mike Ufer ◽

Florian Thiemann ◽

Markus Steinfath ◽

...

Keyword(s):

Receptor Antagonist ◽

Receptor Agonist ◽

Cannabinoid Receptor ◽

Endocannabinoid System ◽

Volatile Anesthetics ◽

Sedative Effect ◽

Additive Interaction ◽

Isobolographic Analysis ◽

Single Drug ◽

Selective Agonists

Background Both propofol and volatile anesthetics have been reported to interact with the endocannabinoid system. The purpose of this study was to evaluate the effect of selective agonists for cannabinoid receptor types 1 and 2 on etomidate-induced sedation. Methods A controlled, blinded, experimental study was performed in 20 mice that received intraperitoneal injections of etomidate, the cannabinoid1 receptor agonist arachidonyl-2-chloroethylamide (ACEA), the cannabinoid2 receptor agonist JWH 133 alone, and both ACEA and JWH 133 combined with etomidate. The cannabinoid1 receptor antagonist AM 251 and the cannabinoid2 receptor antagonist AM 630 were administered 10 min before the delivery of ACEA and JWH 133, respectively. Each drug combination was applied to 6-8 mice of these 20 study animals. Sedation was monitored by a Rota-Rod (Ugo Basile, Comerio, Italy). Isobolographic analysis was used for evaluation of pharmacologic interaction. Results Single drug administration of etomidate and ACEA produced dose- and time-dependent decreased time on the Rota-Rod (P < 0.05). No sedative effect was seen after JWH 133. Etomidate-induced sedation was significantly increased and prolonged with ACEA (P < 0.05), but not with JWH 133. Isobolographic analysis revealed an additive interaction between ACEA and etomidate that was antagonized by the cannabinoid1 receptor antagonist AM 251. The cannabinoid1 receptor antagonist had no effect on etomidate alone. Conclusions Etomidate-induced sedation was increased and prolonged by activation of the cannabinoid1 receptor, but not of the cannabinoid2 receptor, in mice. However, this interaction was only additive.

Download Full-text