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

Cannabinoid receptors are widely distributed in the nuclei of the extrapyramidal motor and mesolimbic reward systems; their exact functions are, however, not known. The aim of the present study was to characterize the effects of cannabinoids on the electrically evoked release of endogenous dopamine in the corpus striatum and the nucleus accumbens. In rat brain slices dopamine release elicited by single electrical pulses was determined by fast cyclic voltammetry. Dopamine release was markedly inhibited by the OP2 opioid receptor agonist U-50488 and the D2/D3 dopamine receptor agonist quinpirole, indicating that our method is suitable for studying presynaptic modulation of dopamine release. In contrast, the CB1/CB2 cannabinoid receptor agonists WIN55212-2 (10(-6) M) and CP55940 (10(-6)-10(-5) M) and the CB1 cannabinoid receptor antagonist SR141716A (10(-6) M) had no effect on the electrically evoked dopamine release in the corpus striatum and the nucleus accumbens. The lack of a presynaptic effect on terminals of nigrostriatal and mesolimbic dopaminergic neurons is in accord with the anatomical distribution of cannabinoid receptors: The perikarya of these neurons in the substantia nigra and the ventral tegmental area do not synthesize mRNA, and hence protein, for CB1 and CB2 cannabinoid receptors. It is therefore unlikely that presynaptic modulation of dopamine release in the corpus striatum and the nucleus accumbens plays a role in the extrapyramidal motor and rewarding effects of cannabinoids.
J Neurochem 1999 Sep
PMID:Effects of cannabinoids on dopamine release in the corpus striatum and the nucleus accumbens in vitro. 1046 98

Since activation of cannabinoid CB1 receptors inhibits gastrointestinal transit in the mouse, this study analyzed the action of the cannabinoid receptor agonist methanandamide on distension-induced propulsive motility. Peristalsis in luminally perfused segments of the guinea-pig isolated ileum was elicited by a rise of the intraluminal pressure. The pressure threshold at which peristaltic contractions were triggered was used to quantify drug effects. Methanandamide (0.1-3 microM) inhibited peristalsis as deduced from a concentration-related increase in the peristaltic pressure threshold, an action that was prevented by the CB1 receptor antagonist SR141716A (1 microM) per se, which had no effect on peristalsis. The distension-induced ascending reflex contraction of the circular muscle was likewise depressed by methanandamide in a SR141716A-sensitive manner, whereas indomethacin-induced phasic contractions of the circular muscle were left unchanged by methanandamide. The anti-peristaltic action of methanandamide was inhibited by apamin (0.5 microM), attenuated by N-nitro-L-arginine methyl ester (300 microM) and left unaltered by suramin (300 microM), pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (150 microM) and naloxone (0.5 microM). It is concluded that methanandamide depresses intestinal peristalsis via activation of CB1 receptors on enteric neurons, which results in blockade of excitatory motor pathways and facilitation of inhibitory pathways operating via apamin-sensitive K+ channels and nitric oxide.
Neuropharmacology 1999 Sep
PMID:Cannabinoid inhibition of guinea-pig intestinal peristalsis via inhibition of excitatory and activation of inhibitory neural pathways. 1047 Oct 82

Cannabinoids, such as marijuana, are known to impair learning and memory perhaps through their actions in the hippocampus where cannabinoid receptors are expressed at high density. Although cannabinoid receptor activation decreases glutamatergic synaptic transmission in cultured hippocampal neurons, the mechanisms of this action are not known. Cannabinoid receptor activation also inhibits calcium channels that support neurotransmitter release in these cells, making modulation of these channels a candidate for cannabinoid-receptor-mediated effects on synaptic transmission. Whole cell patch-clamp recordings of glutamatergic neurons cultured from the CA1 and CA3 regions of the hippocampus were used to identify the mechanisms of the effects of cannabinoids on synaptic transmission. Cannabinoid receptor activation reduced excitatory postsynaptic current (EPSC) size by approximately 50% but had no effect on the amplitude of spontaneous miniature EPSCs (mEPSCs). This reduction in EPSC size was accompanied by an increase in paired-pulse facilitation measured in low (1 mM) extracellular calcium and by a decrease in paired-pulse depression measured in normal (2.5 mM) extracellular calcium. Together, these results strongly support the hypothesis that cannabinoid receptor activation decreases EPSC size by reducing release of neurotransmitter presynaptically while having no effect on postsynaptic sensitivity to glutamate. Further experiments were done to identify the molecular mechanisms underlying this cannabinoid-receptor-mediated decrease in neurotransmitter release. Cannabinoid receptor activation had no effect on the size of the presynaptic pool of readily releasable neurotransmitter-filled vesicles, eliminating reduction in pool size as a mechanism for cannabinoid-receptor-mediated effects. After blockade of Q- and N-type calcium channels with omega-agatoxin TK and omega-conotoxin GVIA; however, activation of cannabinoid receptors reduced EPSC size by only 14%. These results indicate that cannabinoid receptor activation reduces the probability that neurotransmitter will be released in response to an action potential via an inhibition of presynaptic Q- and N-type calcium channels. This molecular mechanism most likely contributes to the impairment of learning and memory produced by cannabinoids and may participate in the analgesic, antiemetic, and anticonvulsive effects of these drugs as well.
J Neurophysiol 1999 Sep
PMID:Mechanisms of cannabinoid-receptor-mediated inhibition of synaptic transmission in cultured hippocampal pyramidal neurons. 1048 47

Anandamide is an endogenous cannabinoid receptor agonist with similar pharmacological effects as D9-tetrahydrocannabinol, the major psychoactive compound in marijuana. Because anandamide does inhibit long-term potentiation, and cannabinoid abuse is known to affect learning and memory, the effects of anandamide on recombinant AMPA glutamate receptor (GluR) subunit currents were studied in Xenopus oocytes. All subunit currents were not affected by SR-1 41716A (a selective CB1 cannabinoid receptor antagonist), but were blocked by the selective AMPA antagonist CNQX and were sensitive to anandamide. Anandamide directly inhibited kainate (KA) activated homomeric GluR1; GluR3 and heteromeric GluR1/3; GluR2/3 receptor currents with IC50 values of 161+/-19, 143+/-12, 148+/-10 and 241+/-107 microM, respectively. The sensitivity of all the subunits to anandamide was not significantly different. Anandamide inhibition was voltage-independent, specific, and could not be duplicated by arachidonic acid or WIN 55,212-2 mesylate. Furthermore, anandamide effects were potentiated by forskolin (an adenylyl cyclase stimulator) and 8-bromo-cAMP (a cAMP analog), whereas MDL-HCl (an adenylyl cyclase inhibitor) caused a reversal of anandamide inhibition of GluR receptor current. Anandamide inhibition appears to be mediated by cAMP synthesis, and may underlie the involvement of this brain cannabinoid agonist in the modulation of fast synaptic transmission in the CNS.
Naunyn Schmiedebergs Arch Pharmacol 1999 Sep
PMID:Anandamide inhibition of recombinant AMPA receptor subunits in Xenopus oocytes is increased by forskolin and 8-bromo-cyclic AMP. 1054 24

Peripheral administration of cannabinoid CB1 receptor agonists to laboratory rats induce a brief rise in plasma prolactin (PRL) levels followed by a prolonged decrease in PRL secretion from the pituitary. While the inhibitory component of this biphasic response depends on the cannabinoid-induced activation of dopamine release from hypothalamic terminals located in the median eminence, the neurobiological mechanisms underlying the activation phase of PRL release remains to be explained. In the present study the possible direct effect of the cannabinoid receptor agonist delta9-Tetrahydrocannabinol (THC) on prolactin secretion and cAMP accumulation was examined in anterior pituitary cultures. THC (0.1 and 1 microM) increased cAMP levels, and induced PRL release (1 and 10 mu). THC did not affect vasoactive intestinal peptide (VIP, 0.5 microM) induced cAMP accumulation in pituitary cultures, showing additive effects at THC 1 microM concentration. However, THC did prevent VIP-dependent increases in prolactin secretion. These results indicate that THC, through a direct pituitary action, activates both the synthesis of cAMP and PRL release and interferes with intracellular mechanisms involved in PRL secretion by VIP. These actions could be mediated through cannabinoid CB1 receptors which were found to be present in anterior pituitary cells, including lactotrophs, as revealed by immunocytochemistry with a specific polyclonal antibody raised against the CB1 receptor protein.
Brain Res 1999 Sep 11
PMID:Effects of delta9-THC on VIP-induced prolactin secretion in anterior pituitary cultures: evidence for the presence of functional cannabinoid CB1 receptors in pituitary cells. 1054 94

Previous research in this laboratory concerning delta9-tetrahydrocannabinol-induced spinal antinociception indicated the critical role of dynorphin A-(1-17) in spinal antinociception following acute intrathecal (i.t.) administration. In the present study, tolerance development to delta9-tetrahydrocannabinol-induced spinal antinociception attenuated delta9-tetrahydrocannabinol-induced modulation of immunoreactive dynorphin A-(1-17). These data indicate that at lower doses of drug, desensitization of the cannabinoid receptor inhibits stimulation of downstream dynorphinergic neurons. However, at higher doses of drug, desensitization is overcome and spinal dynorphin A concentrations are increased by delta9-tetrahydrocannabinol. Antinociception in the absence of elevated dynorphin A-(1-17) levels in the tolerant rat suggests that factors other than the attenuated dynorphin release are components of antinociception in the tolerant state. The shift from the critical role of dynorphin A in cannabinoid antinociception vs. that in the non-tolerant state may indicate tolerance also at the kappa-opioid receptor, a role as yet undetermined.
Eur J Pharmacol 1999 Sep 24
PMID:A diminution of delta9-tetrahydrocannabinol modulation of dynorphin A-(1-17) in conjunction with tolerance development. 1055 77

The effect of delta9-tetrahydrocannabinol (THC), the major psycho-active component of marijuana, in human prostate cancer cells PC-3 was investigated. THC caused apoptosis in a dose-dependent manner. Morphological and biochemical changes induced by THC in prostate PC-3 cells shared the characteristics of an apoptotic phenomenon. First, loss of plasma membrane asymmetry determined by fluorescent anexin V binding. Second, presence of apoptotic bodies and nuclear fragmentation observed by DNA staining with 4',6-diamino-2-phenylindole (DAPI). Third, presence of typical 'ladder-patterned' DNA fragmentation. Central cannabinoid receptor expression was observed in PC-3 cells by immunofluorescence studies. However, several results indicated that the apoptotic effect was cannabinoid receptor-independent, such as lack of an effect of the potent cannabinoid agonist WIN 55,212-2, inability of cannabinoid antagonist AM 251 to prevent cellular death caused by THC and absence of an effect of pertussis toxin pre-treatment.
FEBS Lett 1999 Sep 24
PMID:Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. 1057 Sep 48

The possible therapeutic use of marijuana s active principles, the cannabinoids, is currently being debated. It is now known that these substances exert several of their pharmacological actions by activating specific cell membrane receptors, the CB1 and CB2 cannabinoid receptor subtypes. This knowledge led to the design of synthetic cannabinoid agonists and antagonists with high therapeutic potential. The recent discovery of the endocannabinoids, i.e. endogenous metabolites capable of activating the cannabinoid receptors, and the understanding of the molecular mechanisms leading to their biosynthesis and inactivation, opened a new era in research on the pharmaceutical applications of cannabinoids. Ongoing studies on the pathological and physiological conditions regulating the tissue levels of endocannabinoids, and on the pharmacological activity of these compounds and their derivatives, may provide a lead for the development of new drugs for the treatment of nervous and immune disorders, cardiovascular diseases, pain, inflammation and cancer. These studies are reviewed in this article with special emphasis on the chemical features that determine the interaction of endocannabinoids with the proteins mediating their activity and degradation.
Curr Pharm Des 2000 Sep
PMID:Endocannabinoids: new targets for drug development. 1090 98

During the past several years, cannabinoid biology has witnessed marked advances that has propelled it to the forefront of biomedical research. These new developments have also provided an opportunity to examine the physiological and biochemical events underlying the use and abuse of cannabis as well as elucidating the biological role of the endogenous cannabinoid ligands (endocannabinoids). The biological targets for endocannabinoids include the cannabinoid receptors (CB1 and CB2), the enzyme anandamide amidohydrolase (AAH), and the carrier protein referred to as the anandamide transporter (ANT). The identification of arachidonylethanolamide (anandamide, AEA) as an endogenous cannabinoid has been an important development in cannabinoid research which has led to the identification of two proteins associated with cannabinoid physiology in addition to the CB1 and CB2 receptors. These proteins are anandamide amidohydrolase (AAH), an enzyme responsible for the hydrolytic breakdown of anandamide and the anandamide transporter (ANT), a carrier protein involved in the transport of anandamide across the cell membrane. Evidence obtained so far suggests that these two proteins, in combination, are responsible for the termination of the biological actions of anandamide. Also, the discovery of anandamide has revealed a novel class of more selective agents possessing somewhat different pharmacological properties than the cannabinoids. A number of such analogs have now been reported many of which possess markedly improved cannabinoid receptor affinities and metabolic stabilities compared to those of the parent ligand. Generally, anandamide and all known analogs exhibit significant selectivities with high affinities for the CB1 receptor and modest to very low affinity for the CB2 receptor. In a relatively short period of time, pharmacological and biochemical studies have confirmed initial speculations that anandamide is either a neuromodulator or neurotransmitter and has significantly advanced our understanding of cannabinoid biochemistry. This summary seeks to define the pharmacology of endocannabinoids and to focus on the structure-activity relationships (SAR) of anandamide for the CB1 cannabinoid receptor.
Curr Pharm Des 2000 Sep
PMID:Natural and synthetic endocannabinoids and their structure-activity relationships. 1090 99

The influence of the cannabinoids anandamide, methanandamide and WIN 55212-2 on the delayed rectifier K(+) current (I(K(V))) in rat arterial myocytes was investigated. Anandamide caused a concentration-dependent reduction of total peak and late K(+) current (I(K)). The maximal effect (about 50% inhibition of I(K)) was reached with 3 microM, and half-maximal current block was observed at 0.6 microM. Blockade was voltage-independent. Inhibition of I(K) by the cannabinoid was associated with a characteristic increase in the rate of current relaxation. Methanandamide (10 microM), a metabolically more stable analogue of anandamide, decreased I(K) with a similar time course. Current traces in the presence of the drug also showed an acceleration of inactivation. The presence of TEA did not impair the inhibition by anandamide or methanandamide, but inhibition was prevented by pre-exposure to 4-AP, showing that both cannabinoids inhibited I(K(V)) while having no influence on Ca(2+)-dependent K(+) current (I(K(Ca))). The CB(1) receptor antagonist SR141716A (10 microM) did not influence the action of anandamide or methanandamide. Arachidonic acid (1 microM) increased I(K) considerably. However, in the presence of TEA it caused a decrease of I(K(V)) with a characteristic increase in the rate of current relaxation. WIN 55212-2 (20 microM) caused similar inhibition of I(K). Internally applied anandamide (10 microM) or methanandamide (10 microM) was ineffective at influencing I(K). In the dialyzed cells, the additional external application of a cannabinoid promptly initiated inhibition. The results show that anandamide, methanandamide and WIN 55212-2 affect I(K(V)) in a cannabinoid receptor-independent way similar to that of arachidonic acid, which, unlike the cannabinoids, additionally increases a Ca(2+)-activated K(+) current. It is suggested that cannabinoids might bind to an external site on or near the K(v) channel of the vascular smooth muscle cells.
Br J Pharmacol 2000 Sep
PMID:Influence of cannabinoids on the delayed rectifier in freshly dissociated smooth muscle cells of the rat aorta. 1096 73


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