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PubMed2003

Arachidonylcyclopropylamide increases microglial cell migration through cannabinoid CB2 and abnormal-cannabidiol-sensitive receptors.

Microglial cells, the macrophages of the brain, express low, yet detectable levels of cannabinoid CB(1) receptors, which are known to modulate cell migration. To determine if cannabinoid CB(1) receptors expressed by microglial cells modulate their migration, we assessed whether arachidonylcyclopropylamide (ACPA, an agonist shown to selectively activate CB(1) receptors) affects the migration of BV-2 cells, a mouse microglial cell line. We found that ACPA induced a dose-dependent increase in BV-2 cell migration (EC(50)=2.2 nM). This ACPA response was blocked by pertussis toxin pretreatment, suggesting the involvement of G(i/o) protein-coupled receptors. However, the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) did not prevent ACPA-induced BV-2 cell migration. Two antagonists of cannabinoid CB(2) receptors N-(1,S)-endo-1,3,3-trimethyl bicyclo(2,2,1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) and cannabinol, as well as two antagonists of the newly identified "abnormal-cannabidiol-sensitive" (abn-CBD) receptors (O-1918 and cannabidiol) prevented this response. Our results suggest that cannabinoid CB(2) receptors and abn-CBD receptors, rather than cannabinoid CB(1) receptors, regulate microglial cell migration, and that ACPA is a broad cannabinoid receptor agonist.

Animals↗
PubMed2000

Relative involvement of cannabinoid CB(1) and CB(2) receptors in the Delta(9)-tetrahydrocannabinol-induced inhibition of natural killer activity.

We demonstrated that in vivo administration of Delta(9)-tetrahydrocannabinol in mice (15 mg/kg s.c.) significantly inhibited natural killer cell (NK) cytolytic activity without affecting Concanavalin A (ConA)-induced splenocyte proliferation. Moreover, we investigated the effect of in vivo pretreatment with cannabinoid receptor antagonists, namely, the selective cannabinoid CB(1) receptor antagonist SR 141716 [N-piperidin-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide] and the selective cannabinoid CB(2) receptor antagonist SR 144528 ¿N-[(1S)-endo-1,3, 3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazo le- 3-carboxamide¿, on Delta(9)-tetrahydrocannabinol-induced inhibition of NK cytolytic activity. Both antagonists partially reversed the Delta(9)-tetrahydrocannabinol inhibition of NK cytolytic activity, although the cannabinoid CB(1) receptor antagonist was more effective than the cannabinoid CB(2) receptor antagonist. The parallel measurement of interferon gamma and interleukin 2 levels revealed that Delta(9)-tetrahydrocannabinol significantly reduced (about 70%) the former cytokine without affecting the latter. Cannabinoid CB(1) and CB(2) receptor antagonists completely reversed the interferon gamma reduction induced by Delta(9)-tetrahydrocannabinol. Our results indicate that both types of cannabinoid receptors are involved in the complex network mediating NK cytolytic activity.

Animals↗
PubMed1999

Stimulation of peripheral cannabinoid receptor CB2 induces MCP-1 and IL-8 gene expression in human promyelocytic cell line HL60.

Using the recently developed methodology of nucleic acid microarrays spotted with specific cDNAs probes belonging to different gene families, we showed for the first time that nanomolar concentrations of the cannabinoid ligand CP-55940 upregulated the expression of two different members of the chemokine gene family: the alpha-chemokine interleukin-8 (IL-8) and the beta-chemokine monocyte chemotactic protein-1 (MCP-1), in the promyelocytic cell line HL60 transfected with peripheral cannabinoid receptors (CB2). These genomic modulations observed on large-scale cDNA arrays were first confirmed by Northern blot studies. Furthermore, ELISA evaluations in culture supernatants indicated that the cannabinoid-induced activation of these two chemokine genes was followed by enhanced expression and secretion of the corresponding proteins. These upregulations initially observed in transfected HL60 cells overexpressing CB2 receptors, also occurred in normal non-transfected HL60 cells. The enhancement of IL-8 and MCP-1 gene transcription and protein production was shown to be pertussis toxin sensitive attesting that this phenomenon was a Gi protein-coupled receptor-mediated process as expected for cannabinoid receptors. More specifically, the abolition of the cannabinoid-induced effect by the specific CB2 antagonist SR 144528 indicated a strict peripheral cannabinoid-mediated process. Altogether, our data highlight a possible new function of peripheral cannabinoid receptors in the modulation of immune and inflammatory responses.

Analgesics↗
PubMed1999

The neurobiology of cannabinoid analgesia.

The discovery of cannabinoid receptors and their putative endogenous ligands raises questions as to the nature of the effects produced by cannabinoids on neural circuits that mediate pain and whether endogenous cannabinoids produced by the brain or in the periphery serve naturally to modulate pain. A sizable body of previous work showed that cannabinoid agonists suppress pain behavior in a variety of models of acute and chronic pain. However, at appropriate doses, cannabinoids also profoundly suppress motor behavior (see Sañudo-Peña et al., this volume), which complicates the interpretation of behavioral analgesia since a motor response is the endpoint of virtually all such studies. Studies conducted in this laboratory used biochemical and neurophysiological measures to determine whether cannabinoids suppress nociceptive neurotransmission. The results showed that cannabinoids suppress nociceptive neurotransmission at the level of the spinal cord and the thalamus. These effects are reversible, receptor mediated, selective for painful as opposed to nonpainful somatic stimuli, and track the behavioral analgesia both in time course and potency.

Analgesia↗
PubMed2001

Cannabinoids of diverse structure inhibit two DOI-induced 5-HT(2A) receptor-mediated behaviors in mice.

We have recently shown that the selective cannabinoid CB(1) receptor antagonist SR 141716A produces robust frequencies of head-twitch response (HTR) and ear-scratch response (ESR) in drug-naive mice. Both behaviors were potently blocked by the selective 5-HT(2A/C) receptor antagonist SR 46349B. Selective 5-HT(2A/C) agonists such as DOI also produce these behaviors in mice. The purpose of the present study was to: (1) investigate whether Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and its analogs [Delta(8)-tetrahydrocannabinol (Delta(8)-THC), HU-210, CP 55,940, and WIN 55,212-2] can prevent the DOI-induced behaviors and (2) to see whether any correlation exists in the ID(50) potency order of these cannabinoids in inhibiting the DOI-induced HTR and ESR relative to their published ED(50) potency profiles in producing the tetrad of behaviors in mice. Thus, at 0 min, different groups of mice were injected intraperitoneally with either vehicle or varying doses of the following cannabinoids: Delta(9)-THC (0.25-20 mg/kg), Delta(8)-THC (2.5-20 mg/kg), HU-210 (0.02-0.5 mg/kg), CP 55,940 (0.004-0.5 mg/kg), and WIN 55,212-2 (0.5-10 mg/kg). Twenty minutes later, each mouse received an intraperitoneal injection of DOI (1 mg/kg) and the frequencies of DOI-induced behaviors (mean +/- S.E.M.) were recorded for the next 20 min. The tested cannabinoids reduced the frequencies of both DOI-induced HTR and ESR in a dose-dependent fashion. HU-210 was the most potent inhibitor of HTR, whereas CP 55,940 was most effective against ESR. The ID(50) potency order of cannabinoids in blocking the HTR is: HU-210 > CP 55,940 > WIN 55,212-2 > Delta(9)-THC > Delta(8)-THC, which is identical to their published order of potency in producing the tetrad of behaviors in mice. On the other hand, they had the following ID(50) potency order against the ESR: CP 55,940 > HU-210 > WIN 55,212-2 > Delta(9)-THC > Delta(8)-THC. The tested cannabinoids were 3-30 times more potent in preventing the ESR than the HTR. The data show that cannabinoids inhibit 5-HT(2A) receptor-mediated functions in a potent but differential manner.

Amphetamines↗
PubMed1995

Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics.

Aminoalkylindoles (AAIs) are a novel series of cannabinoid receptor ligands. In this report we disclose the structural features of AAIs which are important for binding to this receptor as measured by inhibition of binding of [3H]Win 55212-2 (5). Functional activity in the mouse vas deferens is also noted and used to distinguish agonists from potential antagonists. The key structural features for potent cannabinoid activity in this series are a bicyclic (naphthyl) substituent at the 3-position, a small (H) substituent at the 2-position, and an aminoethyl (morpholinoethyl) substituent at the 1-position. A 6-bromo analog, Win 54461 (31), has been identified as a potential cannabinoid receptor antagonist. Modeling experiments were done to develop a pharmacophore and also to compare AAI structures with those of classical cannabinoids. The fact that the cannabinoid AAIs arose out of work on a series of cyclooxygenase inhibitors make sense now that an endogenous cannabinoid ligand has been identified which is a derivative of arachidonic acid. Because of their unique structures and physical properties, AAIs provide useful tools to study the structure and function of the cannabinoid receptor(s).

Animals↗
PubMed2000

Influence of cannabinoids on the delayed rectifier in freshly dissociated smooth muscle cells of the rat aorta.

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.

Animals↗
PubMed2005

CB1 cannabinoid receptor-mediated modulation of food intake in mice.

1 Marijuana's appetite-increasing effects have long been known. Recent research suggests that the CB(1) cannabinoid receptor antagonist SR141716A may suppress appetite. This study represents a further, systematic investigation of the role of CB(1) cannabinoid receptors in the pharmacological effects of cannabinoids on food intake. 2 Mice were food-restricted for 24 h and then allowed access to their regular rodent chow for 1 h. Whereas the CB(1) antagonist SR141716A dose-dependently decreased food consumption at doses that did not affect motor activity, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased food consumption at doses that had no effect on motor activity. O-3259 and O-3257, structural analogs of SR141716A, produced effects similar to those of the parent compound. 3 Amphetamine (a known anorectic) and diazepam (a benzodiazepine and CNS depressant) decreased food consumption, but only at doses that also increased or decreased motor activity, respectively. The CB(2) cannabinoid receptor antagonist SR144528 and the nonpsychoactive cannabinoid cannabidiol did not affect food intake nor activity. 4 SR141716A decreased feeding in wild-type mice, but lacked pharmacological activity in CB(1) knockout mice; however, basal food intake was lower in CB(1) knockout mice. Amphetamine decreased feeding in both mouse genotypes. 5 These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or that it may have effects of its own aside from antagonism of cannabinoid effects (e.g., decreased feeding behavior and locomotor stimulation). In either case, these results strongly suggest that CB(1) receptors may play a role in regulation of feeding behavior.

Animals↗
PubMed2006

[Perspectives of cannabinoids in gastroenterology].

In early cultures, extracts of the plant Cannabis sativa were medically used for the treatment of gastrointestinal symptoms like nausea, vomiting, diarrhoea and abdominal pain. In the United States cannabis extracts were frequently used as drugs, e. g., for the treatment of diarrhoea, until around 1920. The possibility of cannabis abuse resulted in a worldwide prohibition and thus the temporary ending of the medical use of cannabinoids. The characterisation of an endogenous cannabinoid system consisting of receptors, endogenous agonists, antagonists and degrading enzymes opens the door for a comeback of cannabinoids in medicine. The clinically proven effects in the treatment of pain, cachexia in conjunction with HIV, or malignant disease and treatment of nausea and vomiting in conjunction with chemotherapy now result in the prescription of cannabinoids as valuable medication. This review will discuss the value of cannabinoids in the treatment of nausea and vomiting, i. e., the indications for which cannabinoids are presently used in gastroenterology. Additionally, this review will discuss potential indications within gastroenterology, where results from basic research or individual observations suggest that a future use of cannabinoids in gastroenterology seems possible.

Cannabinoids↗
PubMed1994

Anandamide (arachidonylethanolamide), a brain cannabinoid receptor agonist, reduces sperm fertilizing capacity in sea urchins by inhibiting the acrosome reaction.

Anandamide (arachidonylethanolamide) is an endogenous cannabinoid receptor agonist in mammalian brain. Sea urchin sperm contain a high-affinity cannabinoid receptor similar to the cannabinoid receptor in mammalian brain. (-)-delta 9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in marihuana, reduces the fertilizing capacity of sea urchin sperm by blocking the acrosome reaction that normally is stimulated by a specific ligand in the egg's jelly coat. We now report that anandamide produces effects similar to those previously obtained with THC in Strongylocentrotus purpuratus in reducing sperm fertilizing capacity and inhibiting the egg jelly-stimulated acrosome reaction. Arachidonic acid does not inhibit the acrosome reaction under similar conditions. The adverse effects of anandamide on sperm fertilizing capacity and the acrosome reaction are reversible. The receptivity of unfertilized eggs to sperm and sperm motility are not impaired by anandamide. Under conditions where anandamide completely blocks the egg jelly-stimulated acrosome reaction, it does not inhibit the acrosome reaction artificially initiated by ionomycin, which promotes Ca2+ influx, and nigericin, which activates K+ channels in sperm. These findings provide additional evidence that the cannabinoid receptor in sperm plays a role in blocking the acrosome reaction, indicate that anandamide or a related molecule may be the natural ligand for the cannabinoid receptor in sea urchin sperm, and suggest that binding of anandamide to the cannabinoid receptor modulates stimulus-secretion-coupling in sperm by affecting an event prior to ion channel opening.

Acrosome↗
PubMed1977

The decomposition of acidic and neutral cannabinoids in organic solvents.

High-pressure liquid chromatography was used to study (a) the relative efficiencies of methanol, chloroform, light petroleum (B.P. 40-60 degrees) and methanol-chloroform (9:1) for extracting neutral and acidic cannabinoids from cannabis resin; (b) the decomposition patterns of the resulting solutions under various storage conditions, and (c) the cannabinoid profile of a cross section through a block of cannabis resin. The results show that (a) methanol is the most effective extracting solvent of those tested; (b) acidic cannabinoids in solution decompose in darkness by varying amounts depending on the temperature, solvent, storage time and particular cannabinoid; (c) neutral cannabinoids in solution are relatively stable in darkness; (d) daylight causes appreciable decomposition of both acidic and neutral cannabinoids in solution, (e) the cannabinoid profile of a resin is complex with lower levels of acidic material in the outer layers.

Cannabinoids↗
PubMed2001

Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review.

OBJECTIVE: To quantify the antiemetic efficacy and adverse effects of cannabis used for sickness induced by chemotherapy. DESIGN: Systematic review. DATA SOURCES: Systematic search (Medline, Embase, Cochrane library, bibliographies), any language, to August 2000. STUDIES: 30 randomised comparisons of cannabis with placebo or antiemetics from which dichotomous data on efficacy and harm were available (1366 patients). Oral nabilone, oral dronabinol (tetrahydrocannabinol), and intramuscular levonantradol were tested. No cannabis was smoked. Follow up lasted 24 hours. RESULTS: Cannabinoids were more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride: relative risk 1.38 (95% confidence interval 1.18 to 1.62), number needed to treat 6 for complete control of nausea; 1.28 (1.08 to 1.51), NNT 8 for complete control of vomiting. Cannabinoids were not more effective in patients receiving very low or very high emetogenic chemotherapy. In crossover trials, patients preferred cannabinoids for future chemotherapy cycles: 2.39 (2.05 to 2.78), NNT 3. Some potentially beneficial side effects occurred more often with cannabinoids: "high" 10.6 (6.86 to 16.5), NNT 3; sedation or drowsiness 1.66 (1.46 to 1.89), NNT 5; euphoria 12.5 (3.00 to 52.1), NNT 7. Harmful side effects also occurred more often with cannabinoids: dizziness 2.97 (2.31 to 3.83), NNT 3; dysphoria or depression 8.06 (3.38 to 19.2), NNT 8; hallucinations 6.10 (2.41 to 15.4), NNT 17; paranoia 8.58 (6.38 to 11.5), NNT 20; and arterial hypotension 2.23 (1.75 to 2.83), NNT 7. Patients given cannabinoids were more likely to withdraw due to side effects 4.67 (3.07 to 7.09), NNT 11. CONCLUSIONS: In selected patients, the cannabinoids tested in these trials may be useful as mood enhancing adjuvants for controlling chemotherapy related sickness. Potentially serious adverse effects, even when taken short term orally or intramuscularly, are likely to limit their widespread use.

Antiemetics↗
PubMed2006

Cannabinoids modulate the P-type high-voltage-activated calcium currents in purkinje neurons.

Endocannabinoids released by postsynaptic cells inhibit neurotransmitter release in many central synapses by activating presynaptic cannabinoid CB1 receptors. In particular, in the cerebellum, endocannabinoids inhibit synaptic transmission at granule cell to Purkinje cell synapses by modulating presynaptic calcium influx via N-, P/Q-, and R-type calcium channels. Using whole cell patch-clamp techniques, we show that in addition to this presynaptic action, both synthetic and endogenous cannabinoids inhibit P-type calcium currents in isolated rat Purkinje neurons independent of CB1 receptor activation. The IC50 for the anandamide (AEA)-induced inhibition of P-current peak amplitude was 1.04 +/- 0.04 microM. In addition, we demonstrate that all the tested cannabinoids in a physiologically relevant range of concentrations strongly accelerate inactivation of P currents. The effects of AEA cannot be attributed to the metabolism of AEA because a nonhydrolyzing analogue of AEA, methanandamide inhibited P-type currents with a similar efficacy. All effects of cannabinoids on P-type Ca2+ currents were insensitive to antagonists of CB1 cannabinoid or vanilloid TRPV1 receptors. In cerebellar slices, WIN 55,212-2 significantly affected spontaneous firing of Purkinje neurons in the presence of CB1 receptor antagonist, in a manner similar to that of a specific P-type channel antagonist, indicating a possible functional implication of the direct effects of cannabinoids on P current. Taken together these findings demonstrate a functionally important direct action of cannabinoids on P-type calcium currents.

Animals↗
PubMed1997

Role of the subthalamic nucleus in cannabinoid actions in the substantia nigra of the rat.

The effect of cannabinoids on the excitatory input to the substantia nigra reticulata (SNr) from the subthalamic nucleus was explored. For this purpose a knife cut was performed rostral to the subthalamic nucleus to isolate the subthalamic nucleus and the SNr from the striatum, a major source of cannabinoid receptors to the SNr. The data showed that the cannabinoid agonist WIN55,212-2 blocked the increase in the firing rate of SNr neurons induced by stimulation of the subthalamic nucleus with bicuculline. Furthermore, the cannabinoid antagonist SR141716A antagonized the effect of the cannabinoid agonist. This study showed that cannabinoids regulate not only the striatonigral pathway, as previously reported, but also the subthalamonigral pathway. The opposite influences of these two inputs to the SNr, inhibitory and excitatory respectively, suggest that endogenous cannabinoids play a major role in the physiological regulation of the SNr.

Analgesics↗
PubMed2004

Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas.

Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether cannabinoids affect it. As a first approach, cDNA array analysis showed that cannabinoid administration to mice bearing s.c. gliomas lowered the expression of various VEGF pathway-related genes. The use of other methods (ELISA, Western blotting, and confocal microscopy) provided additional evidence that cannabinoids depressed the VEGF pathway by decreasing the production of VEGF and the activation of VEGF receptor (VEGFR)-2, the most prominent VEGF receptor, in cultured glioma cells and in mouse gliomas. Cannabinoid-induced inhibition of VEGF production and VEGFR-2 activation was abrogated both in vitro and in vivo by pharmacological blockade of ceramide biosynthesis. These changes in the VEGF pathway were paralleled by changes in tumor size. Moreover, intratumoral administration of the cannabinoid Delta9-tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels and VEGFR-2 activation in the tumors. Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.

Animals↗
PubMed2006

Conformational characteristics of the interaction of SR141716A with the CB1 cannabinoid receptor as determined through the use of conformationally constrained analogs.

Interest in cannabinoid pharmacology increased dramatically upon the identification of the first cannabinoid receptor (CB1) in 1998 and continues to expand as additional endocannabinoids and cannabinoid receptors are discovered. Using CB1 receptor (CB1R) systems, medicinal chemistry programs began screening libraries searching for cannabinoid ligands, ultimately leading to the discovery of the first potent cannabinoid receptor antagonist, SR141716A (Rimonabant). Its demonstrated efficacy in treating obesity and facilitating smoking cessation, among other impressive pharmacological activities, has furthered the interest in cannabinoid receptor antagonists as therapeutics, such that the number of patents and publications covering this class of compounds continues to grow at an impressive rate. At this time, medicinal chemistry approaches including combinatorial chemistry, conformational constraint, and scaffold hopping are continuing to generate a large number of cannabinoid antagonists. These molecules provide an opportunity to gain insight into the 3-dimensional structure-activity relationships that appear crucial for CB1R-ligand interaction. In particular, studies in which conformational constraints have been imposed on the various pyrazole ring substituents of SR141716A provide a direct opportunity to characterize changes in conformation/conformational freedom within a single class of compounds. While relatively few conformationally constrained molecules have been synthesized to date, the structure-activity information is often more readily interpreted than in studies where entire substituents are replaced. Thus, it is the focus of this mini-review to examine the structural properties of SR141716A, and to use conformationally constrained molecules to illustrate the importance of conformation and conformational freedom to CB1R affinity, selectivity, and efficacy.

Drug Interactions↗
PubMed2005

Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum: a combined immunochemical and pharmacological analysis.

Despite the profound effect of cannabinoids on motor function, and their therapeutic potential in Parkinson's and Huntington's diseases, the cellular and subcellular distributions of striatal CB1 receptors are not well defined. Here, we show that CB1 receptors are primarily located on GABAergic (vesicular GABA transporter-positive) and glutamatergic [vesicular glutamate transporter-1 (VGLUT-1)- and VGLUT-2-positive] striatal nerve terminals and are present in the presynaptic active zone, in the postsynaptic density, as well as in the extrasynaptic membrane. Both the nonselective agonist WIN552122 [(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate salt] (EC50, 32 nM) and the CB1-selective agonist ACEA [N-(2-chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide] inhibited [3H]GABA release from rat striatal slices. The effect of these agonists was prevented by the CB1-selective antagonists SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] (1 microM) and AM251 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide trifluoroacetate salt] (1 microM), indicating that cannabinoids inhibit the release of GABA via activation of presynaptic CB1 receptors. Cannabinoids modulated glutamate release via both CB1 and non-CB1 mechanisms. Cannabinoid agonists and antagonists inhibited 25 mM K+-evoked [3H]glutamate release and sodium-dependent [3H]glutamate uptake. Partial involvement of CB1 receptors is suggested because low concentrations of SR141716A partly and AM251 fully prevented the effect of WIN552122 and CP55940 [5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol]. However, the effect of CB1 agonists and antagonists persisted in CB1 knock-out mice, indicating the involvement of non-CB1,CB1-like receptors. In contrast, cannabinoids did not modulate [3H]dopamine release or [3H]dopamine and [3H]GABA uptake. Our results indicate distinct modulation of striatal GABAergic and glutamatergic transmission by cannabinoids and will facilitate the understanding of the role and importance of the cannabinoid system in normal and pathological motor function.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity.

The human cannabinoid receptors, central cannabinoid receptor (CB1) and peripheral cannabinoid receptor (CB2), share only 44% amino acid identity overall, yet most ligands do not discriminate between receptor subtypes. Site-directed mutagenesis was employed as a means of mapping the ligand recognition site for the human CB2 cannabinoid receptor. A lysine residue in the third transmembrane domain of the CB2 receptor (K109), which is conserved between the CB1 and CB2 receptors, was mutated to alanine or arginine to determine the role of this charged amino acid in receptor function. The analogous mutation in the CB1 receptor (K192A) was found to be crucial for recognition of several cannabinoid compounds excluding (R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1, 4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN 55,212-2). In contrast, in human embryonic kidney (HEK)-293 cells expressing the mutant or wild-type CB2 receptors, we found no significant differences in either the binding profile of several cannabinoid ligands nor in inhibition of cAMP accumulation. We identified a high-affinity site for (-)-3-[2-hydroxyl-4-(1, 1-dimethylheptyl)phenyl]-4-[3-hydroxyl propyl] cyclohexan-1-ol (CP-55,940) in the region of helices 3, 6, and 7, with S3.31(112), T3.35(116), and N7.49(295) in the K109A mutant using molecular modeling. The serine residue, unique to the CB2 receptor, was then mutated to glycine in the K109A mutant. This double mutant, K109AS112G, retains the ability to bind aminoalkylindoles but loses affinity for classical cannabinoids, as predicted by the molecular model. Distinct cellular localization of the mutant receptors observed with immunofluorescence also suggests differences in receptor function. In summary, we identified amino acid residues in the CB2 receptor that could lead to subtype specificity.

Alanine↗