Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Morphine and anandamide stimulate the release of nitric oxide (NO) in diverse tissues. The present study examines the consequences of this action on neurotransmitter release in ganglia from two invertebrates: ventral chain ganglia from the leech Hirudo medicinalis and the pedal ganglion from the mussel Mytilus edulis. In these ganglia, preloaded serotonin (5-HT) and dopamine (DA) can be released by 50 mM KCl. Anandamide, an endogenous cannabinoid substance, suppresses the potassium-stimulated release of [3H]DA (80%), but not 5-HT, in a concentration-dependent manner, from the neural tissues of both. The effect of anandamide can be antagonized by pre-exposing the neural tissues of both animals to SR 141716A, a potent cannabinoid receptor antagonist. Prior treatment of the ganglia with N-omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, significantly diminishes the inhibitory effect of anandamide. Morphine also inhibits [3H]DA release in a naloxone- and L-NAME-sensitive manner. Anandamide and morphine act through separate mechanisms since the respective antagonists show no cross-reactivity. The NO donor, SNAP, depressed the potassium-stimulated release of preloaded [3H]DA, but not 5-HT, in the neural tissues of both animals. D-Ala2-Met5 enkephalinamide (DAMA) also inhibited the potassium-stimulated release of [3H]DA in a naloxone-sensitive process. However, the effect of DAMA was seen in the presence of L-NAME (10(-4) M), indicating that the opioid peptide inhibition of the presynaptic release of DA is not coupled to NO. We postulate that cannabinoids and their endogenous effectors play a prominent role in the regulation of catecholamine release in invertebrates via NO release as is the case for opiate alkaloids.
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PMID:Morphine- and anandamide-stimulated nitric oxide production inhibits presynaptic dopamine release. 927 29

Fatty acid amide hydrolase (FAAH) catalyzes the hydrolysis of bioactive fatty acid amides and esters such as the endogenous cannabinoid receptor ligands, anandamide (N-arachidonoyl-ethanolamine) and 2-arachidonoylglycerol, and the putative sleep inducing factor cis-9-octadecenoamide (oleamide). Most FAAH blockers developed to date also inhibit cytosolic phospholipase A2 (cPLA2) and/or bind to the CB1 cannabinoid receptor subtype. Here we report the finding of four novel FAAH inhibitors, two of which, malhamensilipin A and grenadadiene, were screened out of a series of thirty-two different algal natural products, and two others, arachidonoylethylene glycol (AEG) and arachidonoyl-serotonin (AA-5-HT) were selected out of five artificially functionalized polyunsaturated fatty acids. When using FAAH preparations from mouse neuroblastoma N18TG2 cells and [14C]anandamide as a substrate, the IC50s for these compounds ranged from 12.0 to 26 microM, the most active compound being AA-5-HT. This substance was also active on FAAH from rat basophilic leukaemia (RBL-2H3) cells (IC50 = 5.6 microM), and inhibited [14C]anandamide hydrolysis by both N18TG2 and RBL-2H3 intact cells without affecting [14C]anandamide uptake. While AEG behaved as a competitive inhibitor and was hydrolyzed to arachidonic acid (AA) by FAAH preparations, AA-5-HT was resistant to FAAH-catalyzed hydrolysis and behaved as a tight-binding, albeit non-covalent, mixed inhibitor. AA-5-HT did not interfere with cPLA2-mediated, ionomycin or antigen-induced release of [3H]AA from RBL-2H3 cells, nor with cPLA2 activity in cell-free experiments. Finally, AA-5-HT did not activate CB1 cannabinoid receptors since it acted as a very weak ligand in in vitro binding assays, and, at 10-15 mg/kg body weight, it was not active in the 'open field', 'hot plate' and rectal hypothermia tests carried out in mice. Conversely AEG behaved as a cannabimimetic substance in these tests as well as in the 'ring' immobility test where AA-5-HT was also active. AA-5-HT is the first FAAH inhibitor reported to date which is inactive both against cPLA2 and at CB1 receptors, whereas AEG represents a new type of cannabinoid receptor agonist.
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PMID:Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase. 970 57

Dyskinesias following long-term dopamine replacement therapy are a major limitation of current treatments for Parkinson's disease. Recently, attention has been focused on the concept of using non-dopaminergic adjuncts to currently available therapies in an attempt to reduce the problem of dyskinesia. Thus, an enhanced understanding of the neural mechanisms underlying dyskinetic symptoms has led to the realization that it might be possible to manipulate non-dopaminergic systems and reduce dyskinesia without compromising the anti-parkinsonian efficacy of drugs such as L-dopa. This article discusses how non-dopaminergic manipulations could reverse the abnormalities in basal ganglia circuitry responsible for generating dyskinesia. It is proposed that potential anti-dyskinetic drugs might include glutamate (NMDA) receptor antagonists, opioid receptor antagonists, cannabinoid receptor agonists or antagonists, alpha2 adrenergic receptor antagonists, and 5-HT-enhancing agents.
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PMID:Adjuncts to dopamine replacement: a pragmatic approach to reducing the problem of dyskinesia in Parkinson's disease. 982 9

Oleamide (cis-9,10-octadecenoamide) is an endogenous brain lipid which has been suggested to induce sleep in experimental animals. The mechanism of action is unclear but shares many of the characteristics of endogenous cannabinoids such as anandamide and has been shown to enhance in vitro responses to 5-HT and GABA. In the present study we investigated the effects of oleamide on two motor behaviours, back muscle contractions (BMC) and wet-dog shakes (WDS) induced in rats by treatment with the 5-HT2 receptor agonist DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride). We then examined the potential involvement of CB1 cannabinoid receptors in the responses to oleamide and the mechanism of interaction between CB1 and 5-HT2 receptors. Oleamide and the cannabinoid receptor agonist HU210 (6aR)-trans-3-(1,1-dimethylheptyl)6a,7,10,10a-tetrahydro-1-h ydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol) produced a hypolocomotion which was prevented by the CB1 antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride). Despite having no effect alone, oleamide and HU210 potentiated BMC induced by treatment with DOI. SR141716A alone did not affect the response to DOI but it blocked the potentiations caused by oleamide or HU210. WDS were unaffected by oleamide and slightly reduced by HU210. In vitro, oleamide and HU210 enhanced the high affinity binding of 5-HT to 5-HT2 receptors on rat cerebral cortex membranes labelled with 3H-ketanserin. Neither agent, however, altered 5-HT-stimulated phosphoinositide hydrolysis in rat cerebral cortex slices. Oleamide occupied CB1 cannabinoid receptors on rat brain membranes labelled with 3H-CP55940 with an IC50 of 10 microM. The data presented are consistent with oleamide acting via a cannabinoid recognition site to enhance 5-HT2 receptor function in vivo. The mechanism of the modulation is still unclear but it does not appear to involve a potentiation of 5-HT2 receptor-stimulated phosphoinositide hydrolysis.
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PMID:Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors. 1022 57

Estrogens exert effects on mood, mental state, memory and other central nervous system (CNS) functions by modulating neurotransmitter receptor systems in the brain. Studies were designed to investigate the effect of 17beta-estradiol (E(2)) on agonist-stimulated [35S]GTPgammaS binding in membranes to assess the first step in the intracellular signal transduction cascade in a functional assay following: (1) an acute, one-time bolus subcutaneous injection, or (2) 14-day continuous exposure by a slow-release pellet implanted subcutaneously. In rats treated with E(2) acutely, the maximal response produced by activation of serotonin(1A) (5-HT(1A)) receptors was decreased approximately 25% in the hippocampus, cortex, and amygdala. Similarly, acute E(2) administration desensitized 5-HT(1B) and GABA(B) receptors in hypothalamus and cerebellum, respectively, and cannabinoid receptors in hippocampus and cortex. Although the maximal responses were decreased, acute E(2) treatment did not alter the EC(50) of any of the aforementioned receptors. The incubation of membranes prepared from the cortex of ovariectomized (OVX) rats with E(2) (1 microM) in vitro did not alter 5-HT(1A) or cannabinoid receptor-mediated [35S]GTPgammaS binding. By contrast to acute treatment in vivo, 14-day E(2) administration to OVX rats did not alter the maximal responses produced by activation of 5-HT(1A), 5-HT(1B), GABA(B), or cannabinoid receptors in any of the brain regions examined. Thus, it is concluded that acute E(2) administration in vivo modulates multiple G(i/o) coupled receptors in various regions of the female rat brain. Because these effects are observed only in vivo, it is concluded that cytosolic, nuclear and/or extraneuronal factors are required.
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PMID:Acute and long-term effects of 17beta-estradiol on G(i/o) coupled neurotransmitter receptor function in the female rat brain as assessed by agonist-stimulated [35S]GTPgammaS binding. 1071 81

1. The cannabinoid arachidonyl ethanolamide (anandamide) caused concentration-dependent relaxation of 5-HT-precontracted, myograph-mounted, segments of rat left anterior descending coronary artery. 2. This relaxation was endothelium-independent, unaffected by the fatty acid amide hydrolase inhibitor, arachidonyl trifluoromethyl ketone (10 microM), and mimicked by the non-hydrolysable anandamide derivative, methanandamide. 3. Relaxations to anandamide were attenuated by the cannabinoid receptor antagonist, SR 141716A (3 microM), but unaffected by AM 251 (1 microM) and AM 630 (1 microM), more selective antagonists of cannabinoid CB(1) and CB(2) receptors respectively. Palmitoylethanolamide, a selective CB(2) receptor agonist, did not relax precontracted coronary arteries. 4. Anandamide relaxations were not affected by inhibition of sensory nerve transmission with capsaicin (10 microM) or blockade of vanilloid VR1 receptors with capsazepine (5 microM). Nevertheless capsaicin relaxed coronary arteries in a concentration-dependent and capsazepine-sensitive manner, confirming functional sensory nerves were present. In contrast, capsazepine and capsaicin did inhibit anandamide relaxations in methoxamine-precontracted rat small mesenteric arteries. 5. Relaxations to anandamide were inhibited by TEA (1 mM) or iberiotoxin (50 nM), blockers of large conductance, Ca(2+)-activated K(+) channels (BK(Ca)). Gap junction inhibition with 18alpha-glycyrrhetinic acid (100 microM) did not affect anandamide relaxations. 6. This study shows anandamide relaxes the rat coronary artery by a novel mechanism. Anandamide-induced relaxations do not involve the endothelium, degradation into active metabolites, or activation of cannabinoid CB(1) or CB(2) receptors, but may involve activation of BK(Ca). Vanilloid receptor activation also has no role in the effects of anandamide in coronary arteries, even though functional sensory nerves are present.
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PMID:Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries. 1160 34

The purpose of this study was to examine the possible role of cannabinoids on the neuromuscular function of rat gastric fundus. In addition to possible direct effects on smooth muscle, the influence of cannabinoids on contractile (cholinergic) and relaxant (non-adrenergic, non-cholinergic (NANC)) neural innervation of the rat gastric fundus was investigated in vitro. Neither anandamide (an endogenous cannabinoid receptor agonist) nor Win 55,212-2 and methanandamide (synthetic cannabinoid receptor agonists) nor AM 630 (a cannabinoid receptor antagonist) showed any effect on smooth muscle activity at baseline or after precontraction with 5-hydroxytryptamine (5-HT; 10(-7) M). Electrical field stimulation (EFS) of the smooth muscle preparation (40 V; 5 Hz) caused cholinergically mediated twitch contractions that were abolished by atropine (10(-6) M) or tetrodotoxin (TTX; 10(-6) M). Anandamide and Win 55,212-2 reduced these twitch contractions in a concentration-dependent manner, an effect that could be reversed by the cannabinoid receptor antagonist AM 630 for anandamide, but not for Win 55,212-2. When NANC relaxant neural responses (presence of atropine (10(-6) M) and guanethidine (10(-6) M)) were induced by EFS, the cannabinoid receptor agonists anandamide and Win 55,212-2 reduced the relaxant response, an effect that could be reversed by the cannabinoid receptor antagonist AM 630 for anandamide, but not for Win 55,212-2. When given alone AM 630 caused an increase in the EFS-induced relaxant response. The presence of CB1 and CB2 cannabinoid receptor mRNA within the rat stomach was demonstrated by reverse transcription polymerase chain reaction (RT-PCR). The results of this study indicate that cannabinoids modulate excitatory cholinergic and inhibitory NANC neurotransmission in the rat gastric fundus. Endogenous cannabinoids may play a physiological role only in NANC inhibitory transmission, as AM 630 did not modify the electrically induced cholinergic contraction. The involved cannabinoid receptors are most likely located on neuronal structures. The present study also provides evidence that more than one receptor type is involved.
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PMID:Effect of cannabinoids on neural transmission in rat gastric fundus. 1191 Dec 27

Excised outside-out patches from HEK293 cells stably transfected with the human (h) 5-HT3A receptor cDNA were used to determine the effects of cannabinoid receptor ligands on the 5-HT-induced current using the patch clamp technique. In addition, binding studies with radioligands for 5-HT3 as well as for cannabinoid CB1 and CB2 receptors were carried out. The 5-HT-induced current was inhibited by the following cannabinoid receptor agonists (at decreasing order of potency): 9-THC, WIN55,212-2, anandamide, JWH-015 and CP55940. The WIN55,212-2-induced inhibition was not altered by SR141716A, a CB1 receptor antagonist. WIN55,212-3, an enantiomer of WIN55,212-2, did not affect the 5-HT-induced current. WIN55,212-2 did not change the EC50 value of 5-HT in stimulating current, but reduced the maximum effect. The CB1 receptor ligand [3H]-SR141716A and the CB1/CB2 receptor ligand [3H]-CP55940 did not specifically bind to parental HEK293 cells. In competition experiments on membranes of HEK293 cells transfected with the h5-HT3A receptor cDNA, WIN55,212-2, CP55940, anandamide and SR141716A did not affect [3H]-GR65630 binding, but 5-HT caused a concentration dependent-inhibition. In conclusion, cannabinoids stereoselectively inhibit currents through recombinant h5-HT3A receptors independently of cannabinoid receptors. Probably the cannabinoids act allosterically at a modulatory site of the h5-HT3A receptor. Thus the functional state of the receptor can be controlled by the endogenous ligand anandamide. This site is a potential target for new analgesic and antiemetic drugs.
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PMID:Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site. 1238 72

The endocannabinoid 2-arachidonoylglycerol (2-AG) has been shown to activate human platelets in platelet-rich plasma, by binding to a "platelet-type" cannabinoid receptor (CB(PT)). Here, washed human platelets were used to characterize the binding of [(3)H]2-AG to CB(PT), showing a dissociation constant (Kd) of 140 +/- 31 nM and a maximum binding (Bmax) of 122 +/- 10 pmol.mg protein(-1). Selective antagonists of both CB1 and CB2 cannabinoid receptors inhibited this binding, which was enhanced up to approximately 230% over the controls by 1 micro M serotonin (5-hydroxytryptamine, 5-HT). Human platelets were also able to bind [(3)H]5-HT (Kd = 79 +/- 17 nM, Bmax = 14.6 +/- 1.3 pmol.mg protein(-1)), and 1 micro M 2-AG enhanced this binding up to approximately 150%. Moreover, they were able to take up [(3)H]5-HT through a high affinity transporter (Michaelis-Menten constant = 22 +/- 2 nM, maximum velocity = 344 +/- 15 pmol.min(-1).mg protein(-1)), which was not affected by 2-AG. Interestingly, 5-HT did not affect the activity of the 2-AG transporter of human platelets. Treatment of washed platelets with 1 micro M 2-AG led to increased intracellular inositol-1,4,5-trisphosphate (up to approximately 300%) and decreased cyclic AMP (down to approximately 50%). Furthermore, treatment of pre-loaded platelets with 1 micro M 2-AG induced a approximately 300% increase in [(3)H]2-AG release, according to a CBPT-dependent mechanism. Also, 1 micro M 5-HT enhanced the effect of 2-AG on inositol-1,4,5-trisphosphate ( approximately 500% of the controls), cyclic AMP ( approximately 20%) and [(3)H]2-AG release ( approximately 570%), and the latter process was shown to be partly ( approximately 50%) involved in the 5-HT-dependent platelet activation. Taken together, reported findings represent the first demonstration that 2-AG and 5-HT can mutually reinforce their receptor binding on platelet surface, which might have therapeutic implications.
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PMID:Activation of human platelets by 2-arachidonoylglycerol is enhanced by serotonin. 1257 15

(1) On the basis of previous findings that cannabinoids inhibit the function of human and rat 5-HT(3) receptors in vitro, we investigated whether cannabinoid receptor agonists also modulate the activity of the rat peripheral 5-HT(3) receptors on the terminals of cardiopulmonary afferent C-fibres in vivo. (2) In urethane-anaesthetized rats, pre-treated intravenously (i.v.) with the CB(1) receptor antagonist SR 141716A (3 micro mol kg(-1)) and with the beta(1)/beta(2) adrenoceptor antagonist propranolol (0.3-0.4 micro mol kg(-1)), bolus injection of the serotonin 5-HT(3) receptor agonist phenylbiguanide (3-10 micro g kg(-1), i.v.) or the vanilloid VR1 receptor agonist capsaicin (3-10 micro g kg(-1), i.v.) caused an immediate decrease in heart rate and mean arterial blood pressure (the von Bezold-Jarisch reflex). (3) The phenylbiguanide-induced bradycardia was dose-dependently attenuated by the cannabinoid receptor agonists CP 55,940 (0.1-1 micro mol kg(-1), i.v.) and WIN 55,212-2 (0.1-3 micro mol kg(-1), i.v.) 20 min after injection, but not by the inactive S-(-)enantiomer of the latter, WIN 55,212-3 (1 micro mol kg(-1), i.v.). The inhibition was reversible within 30 min. The extent of inhibition by the highest doses of cannabinoid receptor agonists amounted to about 50%. Both cannabinoid receptor agonists failed to affect the capsaicin-evoked bradycardia. (4) In conclusion, our results demonstrate that cannabinoid receptor agonists modulate the von Bezold-Jarisch reflex by inhibiting peripheral serotonin 5-HT(3) receptors in rats in vivo. An analogous mechanism of cannabinoid receptor agonists may be assumed to be involved in other serotonin 5-HT(3) receptor-mediated responses.
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PMID:Cannabinoid receptor-independent inhibition by cannabinoid agonists of the peripheral 5-HT3 receptor-mediated von Bezold-Jarisch reflex. 1264 77


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