Effects of anandamide on cannabinoid receptors in rat brain membranes

Childers, Steven R.; Sexton, Tammy; Roy, Mary Beth

doi:10.1016/0006-2952(94)90134-1

Cited by 164 publications

(107 citation statements)

References 14 publications

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“…The binding of anandamide to cannabinoid receptors leads to the inhibition of adenylyl cyclase and anandamide has been shown to inhibit forskolin-stimulated cyclic AMP accumulation in a number of cell systems expressing the CB1 receptor (Felder et al, 1993;Vogel et al, 1993;Childers et al, 1994). One previous study showed that isoprenaline induced an endothelium-dependent relaxation in rat aortic rings which appeared to be mediated by the release of a CYP-dependent metabolite of arachidonic acid (Satake et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the production of endothelium‐derived hyperpolarizing factor by cannabinoid receptor agonists

Fleming

Schermer

Popp

et al. 1999

British J Pharmacology

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1 The endogenous cannabinoid, anandamide, has been reported to induce an`endothelium-derived hyperpolarizing factor (EDHF)-like' relaxation in vitro. We therefore investigated the e ects of cannabinoid CB1 receptor agonists; HU 210, D 9 -tetrahydrocannabinol (D 9 -THC) and anandamide, and a CB1 antagonist/inverse agonist, SR 141716A, on nitric oxide (NO) and EDHF-mediated relaxation in precontracted rings of porcine coronary, rabbit carotid and mesenteric arteries. 2 In rings of mesenteric artery HU 210 and D 9 -THC induced endothelium-and cyclo-oxygenaseindependent relaxations which were sensitive to SR 141716A. Anandamide (0.03 ± 30 mM) induced a slowly developing, endothelium-independent relaxation which was abolished by diclofenac and was therefore mediated by cyclo-oxygenase product(s). None of the CB1 agonists tested a ected the tone of precontracted rings of rabbit carotid or porcine coronary artery. 3 In endothelium-intact segments, HU 210, D 9 -THC and anandamide did not a ect NO-mediated responses but under conditions of continuous NO synthase/cyclo-oxygenase blockade, signi®cantly inhibited acetylcholine and bradykinin-induced relaxations which are attributed to the production of EDHF. The e ects of HU 210 and D 9 -THC were not observed when experiments were performed in the presence of SR 141716A suggesting the involvement of the CB1 receptor. 4 In a patch clamp bioassay of EDHF production, HU 210 decreased the EDHF-mediated hyperpolarization of detector smooth muscle cells when applied to the donor segment but was without e ect on the membrane potential of detector cells. The inhibition of EDHF production was unrelated to alterations in Ca 2+ -signalling or cytochrome P450 activity. 5 These results suggest that the activation of endothelial CB1 receptors appears to be negatively coupled to the production of EDHF.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the production of endothelium‐derived hyperpolarizing factor by cannabinoid receptor agonists

Fleming

Schermer

Popp

et al. 1999

British J Pharmacology

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“…In several brain areas, including cerebellum and striatum, activation of G-proteins via cannabinoid receptors inhibits basal adenylyl cyclase activity and decreases intracellular levels of cAMP (Bidaut-Russell et al 1990;Pacheco et al 1991;Childers et al 1994). In theory, this decrease in cAMP levels could alter the activity of cAMP-dependent protein kinase, which in turn, could inhibit calcium channel currents.…”

Section: Molecular Mechanisms Underlying G-protein-mediated Effects Omentioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Learning and Memory Impairments Produced by Cannabinoids: Figure 1.

Sullivan

2000

Learn. Mem.

163

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Why does smoking marijuana impair learning and memory? Behavioral studies suggest that a disruption of normal hippocampal function contributes to these deficits. In vitro experiments find that cannabinoid receptor activation reduces neurotransmitter release below the levels required to trigger long-term changes in synaptic strength in the hippocampus. Cannabinoids reduce glutamate release through a G-protein-mediated inhibition of the calcium channels responsible for neurotransmitter release from hippocampal neurons. These mechanisms likely play a role in the learning and memory impairments produced by cannabinoids and by endogenous cannabinoid receptor ligands.

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“…Additionally, a natural brain lipid, N-arachidonoyl ethanolamine, or anandamide, has been characterized as a possible endogenous ligand for the CB 1 receptor (6). Consistent with its postulated role as an endocannabinoid, anandamide (i) binds and activates the CB 1 receptor in vitro (6, 7), (ii) is produced in the brain in response to peripheral pain stimuli (8), and (iii) induces some cannabinoid behavioral effects in vivo, including hypothermia, analgesia, and motor defects (9-11).Although a number of biochemical and cell biological studies have provided evidence that anandamide acts as an endogenous CB 1 ligand (6,7,12,13), the behavioral effects induced by this compound are very weak and transient, especially when compared with those elicited by exocannabinoids like THC (11). Additionally, efforts to block the behavioral effects of anandamide with the CB 1 antagonist SR141716A have met with mixed success (14, 15).…”

mentioning

confidence: 99%

“…Although a number of biochemical and cell biological studies have provided evidence that anandamide acts as an endogenous CB 1 ligand (6,7,12,13), the behavioral effects induced by this compound are very weak and transient, especially when compared with those elicited by exocannabinoids like THC (11). Additionally, efforts to block the behavioral effects of anandamide with the CB 1 antagonist SR141716A have met with mixed success (14, 15).…”

mentioning

confidence: 99%

Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase

Cravatt

Demarest

Patricelli

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

1,197

1,065

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The medicinal properties of marijuana have been recognized for centuries, but clinical and societal acceptance of this drug of abuse as a potential therapeutic agent remains fiercely debated. An attractive alternative to marijuana-based therapeutics would be to target the molecular pathways that mediate the effects of this drug. To date, these neural signaling pathways have been shown to comprise a cannabinoid receptor (CB1) that binds the active constituent of marijuana, tetrahydrocannabinol (THC), and a postulated endogenous CB1 ligand anandamide. Although anandamide binds and activates the CB1 receptor in vitro, this compound induces only weak and transient cannabinoid behavioral effects in vivo, possibly a result of its rapid catabolism. Here we show that mice lacking the enzyme fatty acid amide hydrolase (FAAH ؊/؊ ) are severely impaired in their ability to degrade anandamide and when treated with this compound, exhibit an array of intense CB1-dependent behavioral responses, including hypomotility, analgesia, catalepsy, and hypothermia. FAAH ؊/؊ -mice possess 15-fold augmented endogenous brain levels of anandamide and display reduced pain sensation that is reversed by the CB1 antagonist SR141716A. Collectively, these results indicate that FAAH is a key regulator of anandamide signaling in vivo, setting an endogenous cannabinoid tone that modulates pain perception. FAAH may therefore represent an attractive pharmaceutical target for the treatment of pain and neuropsychiatric disorders.T he endogenous cannabinoid system has been the focus of intense research over the past decade (1-3). Cannabinoid receptors that recognize the active component of marijuana, ⌬ 9 -tetrahydrocannabinol (THC) (4), have been identified in both the brain (CB 1 receptor) and immune system (CB 2 receptor) (5). Additionally, a natural brain lipid, N-arachidonoyl ethanolamine, or anandamide, has been characterized as a possible endogenous ligand for the CB 1 receptor (6). Consistent with its postulated role as an endocannabinoid, anandamide (i) binds and activates the CB 1 receptor in vitro (6, 7), (ii) is produced in the brain in response to peripheral pain stimuli (8), and (iii) induces some cannabinoid behavioral effects in vivo, including hypothermia, analgesia, and motor defects (9-11).Although a number of biochemical and cell biological studies have provided evidence that anandamide acts as an endogenous CB 1 ligand (6,7,12,13), the behavioral effects induced by this compound are very weak and transient, especially when compared with those elicited by exocannabinoids like THC (11). Additionally, efforts to block the behavioral effects of anandamide with the CB 1 antagonist SR141716A have met with mixed success (14, 15). Most recently, anandamide was found to produce significant behavioral effects in CB 1 receptor-knockout (CB 1 Ϫ/Ϫ ) mice (16), suggesting that an alternative site(s) of action for this compound may exist in vivo. On this note, anandamide affects multiple receptor systems in addition to the CB 1 receptor in vitro, i...

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Effects of anandamide on cannabinoid receptors in rat brain membranes

Cited by 164 publications

References 14 publications

Inhibition of the production of endothelium‐derived hyperpolarizing factor by cannabinoid receptor agonists

Inhibition of the production of endothelium‐derived hyperpolarizing factor by cannabinoid receptor agonists

Cellular and Molecular Mechanisms Underlying Learning and Memory Impairments Produced by Cannabinoids: Figure 1.

Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase

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