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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endogenous cannabinoid receptor agonist anandamide is present in central and peripheral tissues. As the kidney contains both the amidase that degrades anandamide and transcripts for anandamide receptors, we characterized the molecular components of the anandamide signaling system and the vascular effects of exogenous anandamide in the kidney. We show that anandamide is present in kidney homogenates, cultured renal endothelial cells (EC), and mesangial cells; these cells also contain anandamide amidase. Reverse-transcriptase PCR shows that EC contain transcripts for cannabinoid type 1 (CB1) receptors, while mesangial cells have mRNA for both CB1 and CB2 receptors. EC exhibit specific, high-affinity binding of anandamide (Kd = 27.4 nM). Anandamide (1 microM) vasodilates juxtamedullary afferent arterioles perfused in vitro; the vasodilation can be blocked by nitric oxide (NO) synthase inhibition with L-NAME (0.1 mM) or CB1 receptor antagonism with SR 141716A (1 microM), but not by indomethacin (10 microM). Anandamide (10 nM) stimulates CB1-receptor-mediated NO release from perfused renal arterial segments; a similar effect was seen in EC. Finally, anandamide (1 microM) produces a NO-mediated inhibition of KCl-stimulated [3H]norepinephrine release from sympathetic nerves on isolated renal arterial segments. Hence, an anandamide signaling system is present in the kidney, where it exerts significant vasorelaxant and neuromodulatory effects.
J Clin Invest 1997 Sep 15
PMID:Production and physiological actions of anandamide in the vasculature of the rat kidney. 929 22

1. The effect of cannabinoid receptor agonists was studied in guinea-pig myenteric neurones in vitro by use of conventional intracellular recording techniques. 2. Exposure of myenteric neurones of the S-cell type to the cannabinoid receptor agonists WIN 55,212-2 (100 nM) and CP 55,940 (100 nM) reversibly and significantly depressed the amplitude of fast excitatory synaptic potentials (fast e.p.s.ps) by 46% and 37%, respectively. 3. The depressant effect of WIN 55,212-2 and CP 55,940 on fast e.p.s.p. amplitude (expressed as the area above the amplitude-time curve (mVs)) was significantly greater than that of the vehicle, Tween 80, which had no detectable effect. 4. The inhibitory effect of WIN 55,212-2 appeared to be concentration-dependent over the range 1-100 nM. WIN 55,212-3, its (-)-enantiomer (100 nM), was inactive. 5. The cannabinoid CB1 receptor antagonist, SR141716A (1 microM), reversed the inhibitory effects of WIN 55,212-2 on fast e.p.s.ps in 38% of neurones tested (3/8) and acetylcholine (ACh)-induced depolarizations in 42% of neurones tested (5/12). 6. When tested on its own, SR141716A (1 microM) caused a 40-50% reduction in the amplitude of fast e.p.s.ps (n = 9). 7. WIN 55,212-2 reversibly depressed the amplitude of the slow e.p.s.p. and, in 2 out of 7 neurones, this effect was reversed by SR141716A (1 microM). 8. It is concluded that cannabinoid-induced inhibition of fast cholinergic synaptic transmission occurred by reversible activation of both presynaptic and postsynaptic CB1 receptors and that slow excitatory synaptic transmission can also be reversibly depressed by cannabinoids. Furthermore, it would seem that subpopulations of myenteric S-neurones and their synapsing cholinergic and non-cholinergic, non-adrenergic terminals are not endowed with cannabinoid receptors.
Br J Pharmacol 1997 Sep
PMID:Effects of cannabinoid receptor ligands on electrophysiological properties of myenteric neurones of the guinea-pig ileum. 931 43

The effects of cannabinoid ligands were studied in rats responding under a repeated acquisition procedure. Each session rats were required to learn a different three-response sequence; every third correct completion of the sequence resulted in the presentation of a food pellet. Errors produced a brief timeout but did not reset the chain. Neither injections of the centrally inactive cannabinoid, cannabidiol (3.2-100 mg/kg i.p.), nor the endogenous ligand, anandamide (0.01-18 mg/kg i.p.), affected rate or accuracy of responding. In contrast, delta9-tetrahydrocannabinol (3.2-18 mg/kg i.p.) and the long-acting analog of the endogenous ligand, R-methanandamide (1-18 mg/kg i.p.), produced dose-related increases in the total percentage of errors and decreases in the rate of responding. The brain cannabinoid receptor antagonist SR141716A (1-32 mg/ kg) did not affect either accuracy or rate of responding when administered alone. A low dose of SR141716A (1 mg/kg), which had no effect when administered alone, antagonized the disruptive effects of delta9-tetrahydrocannabinol and R-methanandamide on rate and accuracy of responding and produced an estimated 3-fold shift to the right in the dose-effect curves. However, administration of SR141716A did not alter the effects of morphine. These results suggest that cannabinoid agonists produce disruptions of learning in rats through stimulation of the cannabinoid receptor. The data further suggest that whereas cannabimimetic agents can disrupt learning, the anandaminergic system may not be tonically involved in learning.
J Pharmacol Exp Ther 1997 Sep
PMID:SR141716A antagonizes the disruptive effects of cannabinoid ligands on learning in rats. 931 68

The separation of the mood-altering effects of cannabinoids from their therapeutic effects has been long sought. Results reported here for a series of C-9 analogs of the cyclic ether O,2-propano-delta 8-tetrahydrocannabinol (O,2-propano-delta 8-THC) point to the C-1 position in classical cannabinoids as a position for which CB2 subtype selectivity occurs within the cannabinoid receptors. O,2-Propano-11-delta 8-THC, O,2-propano delta 9,11-THC, O,2-propano-9-oxo-11-nor-hexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), and O,2-propano-9 alpha- and O,2-propano-9 beta-OH-11-nor-HHC were synthesized and evaluated in radioligand displacement assays for affinity at the CB1 and CB2 receptors and in the mouse vas deferens in vitro assay and the mouse tetrad in vivo assay for cannabinoid activity. Evaluation of binding affinity at the CB1 and CB2 receptors revealed that each compound possesses a modest increased affinity for the CB2 receptor. Analogs which contained an oxygen attached to C-9 (i.e., oxo and hydroxy derivatives) showed the highest affinity and selectivity for CB2 (for O,2-propano-9-oxo-11-nor-HHC, Ki(CB1) = 90 nM, Ki(CB2) = 23 nM, selectivity ratio 3.9; for O,2-propano-9 beta-OH-11-nor-HHC, Ki(CB1) = 26 nM, Ki(CB2) = 5.8 nM, selectivity ratio 4.5). Each compound was found to produce a dose-dependent inhibition of electrically-evoked contractions of the mouse isolated vas deferens when administered at submicromolar concentrations. This inhibition could readily be prevented by the selective CB1 cannabinoid receptor antagonist SR-141716A. The analogs exhibited unique in vivo profiles with O,2-propano-delta 9,11-THC exhibiting antinociception with reduced activity in three other in vivo measures and O,2-propano-9 beta-OH-HHC exhibiting lack of dose responsiveness in all measures. The CB2 selectivities in the O,2-propano analogs may be due to differences in solvation/desolvation that occur when the ligands enter the CB1 vs CB2 binding site. Alternatively, the CB2 selectivities may be a results of an amino acid change from a hydrogen bond-accepting residue in CB1 to a hydrogen bond-donating residue in CB2.
J Med Chem 1997 Sep 26
PMID:Importance of the C-1 substituent in classical cannabinoids to CB2 receptor selectivity: synthesis and characterization of a series of O,2-propano-delta 8-tetrahydrocannabinol analogs. 937 52

The mediator of nitric oxide-(NO) independent vasodilation attributed to endothelium-derived hyperpolarizing factor remains unidentified although there is evidence for a cytochrome P450-derived eicosanoid. Anandamide, the ethanolamide of arachidonic acid and an endogenous ligand for cannabinoid receptors, was proposed as an endothelium-derived hyperpolarizing factor-mediating mesenteric vasodilation to acetylcholine and the hypotensive effect of bradykinin. Using pharmacological interventions that attenuate responses to bradykinin, we examined the possibility of anandamide as a mediator of the NO-independent vasodilator effect of bradykinin in the rat perfused heart by determining responses to anandamide and arachidonic acid. Hearts were treated with indomethacin to exclude prostaglandins and nitroarginine to inhibit NO synthesis and elevate perfusion pressure. The cannabinoid receptor antagonist, SR 141716A (2 microM), reduced dose-dependent vasodilator responses to anandamide (1-10 microgram) but was without effect on responses to AA (1-10 microgram), bradykinin (10-1000 ng) or cromakalim (1-10 microgram). Inhibition of voltage-dependent Ca++ channels with nifedipine (5 nM) attenuated vasodilation to anandamide and arachidonic acid whereas inhibition of Ca++-activated K+ channels with charybdotoxin (10 nM) reduced responses to arachidonic acid but had no effect on vasodilation induced by anandamide. Inhibition of cytochrome P450 with clotrimazole (1 microM) greatly reduced vasodilator responses to bradykinin with less effect on those to anandamide. Finally, the time course of the coronary vasodilator responses to anandamide and bradykinin were dissimilar. These results argue against a role of anandamide in the vasodilator effect of bradykinin in the rat heart.
J Pharmacol Exp Ther 1998 Sep
PMID:Evidence against anandamide as the hyperpolarizing factor mediating the nitric oxide-independent coronary vasodilator effect of bradykinin in the rat. 973 71

We have recently found that cannabinoid receptor binding and gene expression markedly decreased in extrapyramidal structures of aged rats. The present study was designed to analyze the possible existence of similar aging-induced changes in cannabinoid receptor binding and gene expression in brain regions other than extrapyramidal areas, but that also contain a significant population of cannabinoid receptors, such as the cerebellum, hippocampal structures, limbic and hypothalamic nuclei, the cerebral cortex and others. To this end, we analyzed cannabinoid receptor binding, using autoradiography, and cannabinoid receptor mRNA levels, using in situ hybridization, in slide-mounted brain sections obtained from young (3 month old) and aged (> 2 year old) rats. Results were as follows. In the cerebellum, aged rats exhibited a marked decrease in cannabinoid receptor binding in the molecular layer (-33.3%), although accompanied by no changes in mRNA levels in the granular layer. In the cerebral cortex, a small, although statistically significant, decrease in binding was found in the deep layer (VI) (-18.3%) of aged rats, whereas no changes were found in the superficial layer (I). As in the case of the cerebellum, mRNA levels did not change in the cerebral cortex layers (II-III and V-VI). The different regions of the Ammon's horn of the hippocampus exhibited similar cannabinoid receptor binding levels in aged and young rats. Interestingly, mRNA levels decreased in aged rats to a small, but statistically significant, extent (CA1: -26.1%; CA2: -21.6%; CA3: -14.4%). This was also seen in another hippocampal structure, the dentate gyrus (-14.6%), although in this region binding levels increased in aged rats (+28.4%). Two hypothalamic structures, the arcuate nucleus and the ventromedial hypothalamic nucleus, exhibited decreased cannabinoid receptor binding in aged rats (-31.1% and -30.3%, respectively), but this was not seen in the medial preoptic area. This was accompanied by no changes in mRNA levels in the ventromedial hypothalamic nucleus. In the limbic structures, aged rats exhibited similar binding levels to young rats. This was seen in the nucleus accumbens, septum nuclei and basolateral amygdaloid nucleus. However, mRNA levels slightly decreased in the basolateral amygdaloid nucleus (-13.4%), whereas they were not altered in the septum nuclei. Finally, other brain structures, such as the central gray substance and the brainstem, exhibited similar binding levels in aged and young rats. However, it is important to note that mRNA levels increased significantly (+211.2%) in the brainstem of aged rats, an area where the levels of binding and mRNA were very low in young rats. This marked increase may be related to an increase in the presence of glial elements in this region, as revealed by the increase in the immunoreactivity for glial fibrillary acidic protein observed in the brainstem of aged rats as compared to young animals. In summary, senescence was associated with changes in cannabinoid receptors in the cerebellum, the cerebral cortex, limbic and hypothalamic structures, the hippocampus and other brain regions. However, the changes observed (i) were not as marked and relevant as those early reported in extrapyramidal areas, and (ii) exhibited regional differences that might be attributed to the different roles played by these receptors in each region. Of particular relevance by their magnitude were the aging-induced decrease in binding found in the cerebellum and the hypothalamus, and the increase in mRNA levels observed in the brainstem. The latter might be related to an increase in the presence of glial cells which might contain cannabinoid receptor mRNA.
Biochim Biophys Acta 1998 Sep 30
PMID:Changes in cannabinoid receptor binding and mRNA levels in several brain regions of aged rats. 974 81

delta9-Tetrahydrocannabinol (THC), the major active component of marijuana, induced apoptosis in C6.9 glioma cells, as determined by DNA fragmentation and loss of plasma membrane asymmetry. THC stimulated sphingomyelin hydrolysis in C6.9 glioma cells. THC and N-acetylsphingosine, a cell-permeable ceramide analog, induced apoptosis in several transformed neural cells but not in primary astrocytes or neurons. Although glioma C6.9 cells expressed the CBI cannabinoid receptor, neither THC-induced apoptosis nor THC-induced sphingomyelin breakdown were prevented by SR141716, a specific antagonist of that receptor. Results thus show that THC-induced apoptosis in glioma C6.9 cells may rely on a CBI receptor-independent stimulation of sphingomyelin breakdown.
FEBS Lett 1998 Sep 25
PMID:Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. 977 84

Anandamide, an endogenous ligand at the CB1 cannabinoid receptor and palmitoylethanolamide (a putative endogenous ligand at the CB2 receptor) have both been shown to possess anti-hyperalgesic properties in models of somatic and visceral inflammation. In the turpentine-inflamed rat urinary bladder a reversal of the inflammation-associated viscero-visceral hyperreflexia (VVH) was observed when the cannabinoids were administered 135 min after the induction of inflammation. Therefore, in this study we determined the efficacy of these two N-acylethanolamides in the prevention of VVH in the same model, using a prophylactic dosing regimen. Palmitoylethanolamide did not prevent the VVH (in the dose range 10-30 mg/kg, i.a), but anandamide attenuated the response in a dose related manner, with a threshold of 25 mg/kg (i.a). These findings provide further support for an acute anti-nociceptive and anti-hyperalgesic role for CB1 receptor agonists, with CB2 agonist effects only becoming important once the effects of inflammation are established.
Neurosci Lett 1998 Sep 04
PMID:The endogenous cannabinoid anandamide, but not the CB2 ligand palmitoylethanolamide, prevents the viscero-visceral hyper-reflexia associated with inflammation of the rat urinary bladder. 977 65

The effects of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assessed in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, delta9-tetrahydrocannabinol and arachidonylethanolamide (anandamide), or chronic treatment with delta9-tetrahydrocannabinol. As previously reported, acute intravenous (i.v.) injected delta9-tetrahydrocannabinol produced dose-dependent cannabinoid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was distinctly different in that it produced a loss of muscle tone and considerable sedation with little static ataxia, prancing, or incoordination. Despite these qualitative differences between the two agonists, SR 141716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A was able to precipitate a withdrawal syndrome in delta9-tetrahydrocannabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by anandamide, which was not blocked by SR 141716A, precluded conducting dependence studies with this drug. The delta9-tetrahydrocannabinol precipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless behavior and trembling. This is the first demonstration of a precipitated withdrawal syndrome in a non-rodent species.
Eur J Pharmacol 1998 Sep 18
PMID:Effects of SR 141716A after acute or chronic cannabinoid administration in dogs. 979 29

Structure-activity relation studies have established that the alkyl side chain in tetrahydrocannabinol (THC) plays a crucial role in the activation of the cannabinoid receptor. Unfortunately, the flexible nature of this side chain has hampered efforts to elucidate the precise nature of the interaction of THC with its receptors. Therefore, a series of analogs with structurally restrained side chains of varying length was synthesized and evaluated for pharmacological potency in mice and for receptor affinity. The introduction of cis double bonds inserted rigid angles, whereas triple bonds developed regions of planarity. Receptor affinity for the acetylenic and saturated side chains were the same, whereas double bond substitution increased affinity 10-fold. Moreover, the relationship between receptor affinity and potency was 10-fold less than that of Delta(8)-THC in the case of some acetylenic derivatives, whereas changing the triple bond to a double bond restored the potency/affinity ratio. Additionally, an acetylene at C2-C3 in the octyl and nonyl side chains favored antinociception by as much as 70-fold. Surprisingly, several high-affinity acetylenic derivatives, especially those with cyano substitutions at the terminus of the side chain, were partial agonists or were inactive. Some of these low-efficacy, high-affinity ligands elicited antagonistic activity. The finding that manipulations of the side chain produces high- affinity ligands with either antagonist, partial agonist, or full agonist effects reveals a critical structural feature for receptor activation.
J Pharmacol Exp Ther 1999 Sep
PMID:Manipulation of the tetrahydrocannabinol side chain delineates agonists, partial agonists, and antagonists. 1045 79


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