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Results for “Receptor, Cannabinoid, CB2”

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PubMed2005

Targeting the cannabinoid CB2 receptor: mutations, modeling and development of CB2 selective ligands.

Since the discovery of the cannabinoid CB2 receptor in 1993, there has been a growing interest to clarify the importance of this G-protein coupled receptor (GPCR) for human physiology, and to investigate it as a possible target for current and future drug development. Several mutation studies have examined the receptor activation and structure of the receptor binding cavity. Additionally, 3D models for the CB2 receptor have been constructed to aid in perceiving important ligand-receptor interactions. In recent years, many research groups have succeeded in synthesizing new CB2 selective ligands. This review focuses on (i) important features for ligand recognition and/or receptor activation at CB2, derived from mutation and modeling studies, and (ii) recent advances in the field of CB2 selective ligands.

Animals↗

PubMed2006

Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice.

The possible involvement of 2-arachidonoylglycerol (2-AG), an endogenous ligand for the cannabinoid receptors (CB1 and CB2), in contact dermatitis in mouse ear was investigated. We found that the level of 2-AG was markedly elevated in the ear following a challenge with oxazolone in sensitized mice. Of note, the swelling following the challenge was suppressed by either the administration of SR144528, a CB2 receptor antagonist, immediately after sensitization, or the administration of SR144528 upon the challenge. The effect of AM251, a CB1 receptor antagonist, was marginal in either case. It seems apparent, therefore, that the CB2 receptor and its endogenous ligand 2-AG are closely involved in both the sensitization phase and the elicitation phase of oxazolone-induced contact dermatitis. In line with this, we found that Langerhans cells (MHC class II(+)) contain a substantial amount of CB2 receptor mRNA, whereas keratinocytes (MHC class II(-)) do not. We also obtained evidence that the expression of mRNAs for proinflammatory cytokines following a challenge with oxazolone was markedly suppressed by treatment with SR144528. We next examined whether the CB2 receptor and 2-AG participate in chronic contact dermatitis accompanied by the infiltration of tissues by eosinophils. The amount of 2-AG in mouse ear dramatically increased following repeated challenge with oxazolone. Importantly, treatment with SR144528 attenuated both the recruitment of eosinophils and ear swelling in chronic contact dermatitis induced by repeated challenge with oxazolone. These results strongly suggest that the CB2 receptor and 2-AG play important stimulative roles in the sensitization, elicitation, and exacerbation of allergic inflammation.

Animals↗

PubMed2006

Bacterial expression of functional, biotinylated peripheral cannabinoid receptor CB2.

A biotin-protein ligase recognition site (BRS) was inserted into a polypeptide comprised of the maltose-binding protein, the peripheral cannabinoid receptor (CB2), thioredoxin A, and a polyhistidine tag at the carboxy terminus. Expression levels of the recombinant receptor in Escherichia coli BL21(DE3) cells were approximately 1mg per liter of bacterial culture. The biotinylated CB2-fusion fully retained its ligand-binding capacity. Introduction of the BRS at the C-terminus of the CB2 fusion protein (construct CB2-109) resulted in its complete in vivo biotinylation; the biotinylated protein was streptavidin-binding competent. Positioning of the BRS near the N-terminus of CB2 (CB2-112) resulted in a very low level of biotinylation in vivo. However, the detergent solubilized and purified CB2-112 fusion protein were successfully biotinylated in vitro by action of a BirA biotin-protein ligase. The biotinylated CB2-112 fusion protein was cleaved by the tobacco etch virus protease at specifically inserted sites, and deposited onto monomeric avidin agarose beads. Biotinylation of the recombinant CB2 receptor enabled not only purification but also immobilization of the GPCR on a solid support in homogeneous orientation which is beneficial for subsequent structural characterization.

Binding, Competitive↗

PubMed2007

Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors.

BACKGROUND AND PURPOSE: There is increasing evidence to suggest that cannabis can ameliorate muscle-spasticity in multiple sclerosis, as was objectively shown in experimental autoimmune encephalomyelitis models. The purpose of this study was to investigate further the involvement of CB1 and CB2)cannabinoid receptors in the control of experimental spasticity. EXPERIMENTAL APPROACH: Spasticity was induced in wildtype and CB1-deficient mice following the development of relapsing, experimental autoimmune encephalomyelitis. Spastic-hindlimb stiffness was measured by the resistance to flexion against a strain gauge following the administration of CB1 and CB2 agonists. KEY RESULTS: As previously suggested, some CB2-selective agonists (RWJ400065) could inhibit spasticity. Importantly, however, the anti-spastic activity of RWJ400065 and the therapeutic effect of non-selective CB1/CB2 agonists (R(+)WIN55,212-2 and CP55, 940) was lost in spastic, CB1-deficit mice. CONCLUSIONS AND IMPLICATIONS: The CB1 receptor controls spasticity and cross-reactivity to this receptor appears to account for the therapeutic action of some CB2 agonists. As cannabinoid-induced psychoactivity is also mediated by the CB1 receptor, it will be difficult to truly dissociate the therapeutic effects from the well-known, adverse effects of cannabinoids when using cannabis as a medicine. The lack of knowledge on the true diversity of the cannabinoid system coupled with the lack of total specificity of current cannabinoid reagents makes interpretation of in vivo results difficult, if using a purely pharmacological approach. Gene knockout technology provides an important tool in target validation and indicates that the CB1 receptor is the main cannabinoid target for an anti-spastic effect.

Animals↗

PubMed2006

Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain.

Until recently the cannabinoid CB2 receptor was believed to be absent from the central nervous system. In this study we have identified CB2 expressing cells that appear in the rat brain following stroke and hypoxic-ischemia. At 3 days following surgery CB2-positive macrophages, deriving from resident microglia and/or invading monocytes appear on the lesioned side of the brain. By day 7, a mixed population of CB2-positive cells is present. Microglia-derived macrophages are the key cells in the first stages of brain inflammation, and a pivotal step in the neurodegeneration that follows the acute stage of injury. Thus, CB2 may be important in the brain during injury, and in inflammatory neurodegenerative disorders. The presence of CB2-positive cells in the brain following stroke may provide a novel strategy for cannabinoid-mediated intervention into stroke induced neurodegeneration without the psychoactive effects of CB1 receptor stimulation.

Animals↗

PubMed2005

Cannabinoid CB2 receptor agonist activity in the hindpaw incision model of postoperative pain.

The identification of peripherally expressed CB2 receptors and reports that the selective activation of cannabinoid CB2 receptors produces antinociception without traditional cannabinergic side effects suggests that selective cannabinoid CB2 receptor agonists might be useful in the management of pain. In a rat hindpaw incision model, we examined the antiallodynic activity of the selective cannabinoid CB2 receptor agonists AM1241 (3-30 mg/kg i.p.), GW405833 (3-30 mg/kg i.p.), and HU-308 (0.3-30 mg/kg i.p.). The rank order for efficacy in the hindpaw incision model following a dose of 10 mg/kg, i.p. was AM1241 > GW405833 = HU-308, and the selective cannabinoid CB2 receptor antagonist, SR144528, reversed the antiallodynic effect of HU-308. Together, these data suggest that selective cannabinoid CB2 receptor agonists might represent a new class of postoperative analgesics.

Animals↗

PubMed2004

Activation of cannabinoid CB2 receptors suppresses C-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation.

Effects of the CB2-selective cannabinoid agonist AM1241 on activity evoked in spinal wide dynamic range (WDR) neurons by transcutaneous electrical stimulation were evaluated in urethane-anesthetized rats. Recordings were obtained in both the absence and the presence of carrageenan inflammation. AM1241, administered intravenously or locally in the paw, suppressed activity evoked by transcutaneous electrical stimulation during the development of inflammation. Decreases in WDR responses resulted from a suppression of C-fiber-mediated activity and windup. Abeta- and Adelta-fiber-mediated responses were not reliably altered. The AM1241-induced suppression of electrically evoked responses was blocked by the CB2 antagonist SR144528 but not by the CB1 antagonist SR141716A. AM1241 (33 microg/kg intraplantar [i.p.l.]), administered to the carrageenan-injected paw, suppressed activity evoked in WDR neurons relative to groups receiving vehicle in the same paw or AM1241 in the opposite (noninflamed) paw. The electrophysiological effects of AM1241 (330 microg/kg intravenous [i.v.]) were greater in rats receiving i.p.l. carrageenan compared with noninflamed rats receiving an i.p.l. injection of vehicle. AM1241 failed to alter the activity of purely nonnociceptive neurons recorded in the lumbar dorsal horn. Additionally, AM1241 (330 microg/kg i.v. and i.p.l.; 33 microg/kg i.p.l.) reduced the diameter of the carrageenan-injected paw. The AM1241-induced decrease in peripheral edema was blocked by the CB2 but not by the CB1 antagonist. These data demonstrate that activation of cannabinoid CB2 receptors is sufficient to suppress neuronal activity at central levels of processing in the spinal dorsal horn. Our findings are consistent with the ability of AM1241 to normalize nociceptive thresholds and produce antinociception in inflammatory pain states.

Analgesics↗

PubMed2002

CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain.

The cannabinoid agonist, HU210 has been evaluated in vivo in nociceptive and inflammatory pain models in the rat. The ED50 for the anti-nociceptive (increasing mechanical withdrawal threshold) effect was 0.1 mg/kg-1 i.p., and for anti-hypersensitivity and anti-inflammatory activity was 5 g/kg-1 i.p. (in the carrageenan model). The selective CB1 antagonist, AM281 (0.5 microg/kg-1 i.p.) reversed effects of HU210 (10 and 30 microg/kg-1 i.p.) in both nociceptive and inflammatory models of hypersensitivity. The selective CB2 antagonist, SR144528 (1 mg/kg-1 i.p.) antagonised effects of HU210 (30 microg/kg-1 i.p.) in the carrageenan induced inflammatory hypersensitivity. The CB2 agonist, 1-(2,3-Dichlorobenzoyl)-5-methoxy-2-methyl-(2-(morpholin-4-yl)ethyl)-1H-indole (GW405833) inhibited the hypersensitivity and was anti-inflammatory in vivo. These effects were blocked by SR144528. These findings suggest that CB1 receptors are involved in nociceptive pain and that both CB1 and CB2 receptors are involved in inflammatory hypersensitivity. Future studies will investigate effects on identified inflammatory cells within the inflamed tissue to further elucidate the role of cannabinoid receptors.

Acute Disease↗

PubMed2005

Identification of WIN55212-3 as a competitive neutral antagonist of the human cannabinoid CB2 receptor.

1. Several G protein-coupled receptors (GPCRs), including cannabinoid CB(1) and CB(2) receptors, show constitutive activity under heterologous expression. Such a tonic response is generated in the absence of an activating ligand, and can be inhibited by inverse agonists. Neutral antagonists, however, are silent at such receptors, but can reverse both agonist and inverse agonist responses. To date, no neutral antagonist for the CB(2) receptor has been reported. 2. Here, by monitoring receptor-dependent G protein activation, we demonstrate that WIN55212-3 acts as a neutral antagonist at the human CB(2) (hCB(2)) receptor. WIN55212-3 alone, at concentrations </=10(-4) M, behaved as a silent ligand exhibiting no agonist or inverse agonist activity. However, WIN55212-3 competitively antagonized cannabinoid agonist CP-55,940-stimulated responses (pA(2) 6.1). Importantly, the inverse agonism evoked by SR144528 in hCB(2) was dose-dependently reversed by WIN55212-3 (pEC(50) 5.3+/-0.2), indicating true neutral antagonist behavior. 3. Furthermore, WIN55212-3 also antagonized CB(1) receptor signaling in a competitive manner (pA(2) 5.6), but behaved as a partial inverse agonist (pIC(50) 5.5+/-0.1) at the constitutively active human CB(1). 4. Additionally, WIN55212-3 antagonized signaling of the human melatonin MT(1) receptor, with modest activity at the human muscarinic M4 receptor, but it was inactive towards several other GPCRs. 5. These data identify WIN55212-3 as a true neutral hCB(2) receptor antagonist. WIN55212-3 offers a valuable tool for further characterization of ligand activities at the CB(2) receptor and may serve as a lead compound in further efforts to develop more potent and selective neutral CB(2) receptor antagonists.

Animals↗

PubMed2004

Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study.

Two types of cannabinoid receptors have been characterized so far, CB1 and CB2. While CB1 receptors are present both in the CNS and in the periphery, CB2 receptors showed an almost exclusive distribution within the immune system. We now report that CB2 receptors are present in a specific microglial cell type of the human cerebellum. Thus, we have performed immunohistochemical analysis of tissue sections of white matter areas of the human cerebellum and detected the presence of CB2 receptors in perivascular microglial cells. These findings match with the well-known immunomodulatory role of CB2 receptors and open new perspectives on the possible role that these receptors may play in pathophysiological events.

Adult↗

PubMed2006

Involvement of cannabinoid CB2 receptors in the IgE-mediated triphasic cutaneous reaction in mice.

Involvement of cannabinoid CB2 receptors in the IgE-mediated cutaneous reaction was investigated. Epicutaneous challenge with 2,4-dinitrofluorobenzene caused a triphasic swelling in the ear of BALB/c and C57BL/6 mice passively sensitized with anti-dinitrophenol IgE. Peak responses of the ear swelling appeared at 1 h, 24 h, and 8 days after the challenge in both strains of mice. In contrast, cannabinoid CB2 receptor-deficient mice failed to exhibit the obvious triphasic ear swelling observed in wild-type mice. Oral administration of cannabinoid CB2 receptor antagonist/inverse agonists [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide} (SR144528) at doses of 0.1-10 mg/kg significantly and dose-dependently suppressed all three phases of ear swelling in BALB/c mice. Interestingly, epicutaneous treatment with an ether-linked analogue of endogenous cannabinoids, 2-arachidonoylglycerol, caused an ear swelling that could be detected at 1 h, 24 h, and 8 days after treatment of both BALB/c and C57BL/6 mice. These results suggest that cannabinoid CB2 receptors are involved in induction of the triphasic cutaneous reaction mediated by IgE, and that cannabinoid CB2 receptor antagonist/inverse agonists may serve as anti-allergic agents in the treatment of allergic dermatitis.

Animals↗

PubMed2005

Triaryl bis-sulfones as a new class of cannabinoid CB2 receptor inhibitors: identification of a lead and initial SAR studies.

A novel class of cannabinoid CB2 receptor ligands is described. These triaryl bis-sulfones are nanomolar inhibitors of the CB2 receptor and show high selectivity over the cannabinoid CB1 receptor. One example of this new class decreases ligand-induced GTPgammaS binding to recombinant CB2 cell membranes, identifying the compound as a CB2-selective inverse agonist.

Amides↗

PubMed2006

Cannabinoid CB2 receptor: a new target for controlling neural cell survival?

Two types of cannabinoid receptor have been cloned and characterized. Whereas CB1 receptors are ubiquitously expressed in neurons of the CNS, CB2 receptors have been thought to be absent from the CNS. Recent data now question this notion and support the expression of CB2 receptors in microglial cells, astrocytes and even some neuron subpopulations. This discrete distribution makes CB2 receptors interesting targets for treating neurological disorders because CB2-selective agonists lack psychoactivity. Here, we review evidence supporting the idea that CB2 receptors are implicated in the control of fundamental neural cell processes, such as proliferation and survival, and that their pharmacological manipulation might be useful for both delaying the progression of neurodegenerative disorders and inhibiting the growth of glial tumors.

Animals↗

PubMed2005

Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study.

Reports of cannabinoid CB2 receptor protein in the brain have been ambiguous. We therefore tested for CB2 immunoreactivity in the rat brain using immunofluorescence. We detected CB2 labeling in fine fibers in the granule layer. This CB2 labeling did not co-localise with the astrocyte marker glial fibrillary acidic protein (GFAP) and, therefore, the CB2-positive fibers were not astrocytes and were possibly microglial or neuronal. Additionally, strong CB2 labeling was detected in capillary endothelia in the granule, Purkinje cell, and molecular layers. Our results suggest that the role of CB2 receptors in the brain may have been previously underestimated.

Animals↗

PubMed2003

Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation.

1. There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C-fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve-mediated responses. 2. We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE2 on isolated guinea-pig and human vagus nerve preparations, and the cough reflex in conscious guinea-pigs. 3. The non-selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea-pig vagus nerve induced by hypertonic saline, capsaicin and PGE2. These responses were abolished by the CB2 receptor antagonist SR144528, and unaffected by the CB1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin-evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528. 4. Using a guinea-pig in vivo model of cough, JWH 133 (10 mg kg-1, i.p., 20 min) significantly reduced citric acid-induced cough in conscious guinea pigs compared to those treated with the vehicle control. 5. These data show that activation of the CB2 receptor subtype inhibits sensory nerve activation of guinea-pig and human vagus nerve, and the cough reflex in guinea-pigs, suggesting that the development of CB2 agonists, devoid of CB1-mediated central effects, will provide a new and safe antitussive treatment for chronic cough.

Animals↗

PubMed2006

The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB2 receptors.

BACKGROUND AND PURPOSE: 2-arachidonoyl glycerol (2-AG) is an endogenous cannabinoid with central antinociceptive properties. Its degradation is catalysed by monoacylglycerol lipase (MGL) whose activity is inhibited by URB602, a new synthetic compound. The peripheral antinociceptive effects of 2-AG and URB602 in an inflammatory model of pain are not yet determined. We have evaluated these effects with and without the cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists. EXPERIMENTAL APPROACH: Inflammation was induced in rat hind paws by intraplantar injection of formalin. Nociception was assessed behaviourally over the next 60 min, in 19 experimental groups: (1) control; (2-6) 2-AG (0.01-100 microg); (7) AM251 (80 microg); (8) AM251+2-AG (10 microg); (9) AM630 (25 microg); (10) AM630+2-AG (10 microg); (11-16) URB602 (0.1-500 microg); (17) 2-AG+URB602 (ED(50)); (18) AM251+URB602 (ED(50)); (19) AM630+URB602 (ED(50)). Drugs were injected s.c. in the dorsal surface of the hind paw (50 microl), 15 min before formalin injection into the same paw. KEY RESULTS: 2-AG and URB602 produced dose-dependent antinociceptive effects for the late phases of the formalin test with ED(50) of 0.65+/-0.455 mug and 68+/-14.3 microg, respectively. Their combination at ED(50) doses produced an additive antinociceptive effect. These effects were inhibited by AM630 but not by AM251 for 2-AG and by the two cannabinoid antagonists for URB602. CONCLUSIONS AND IMPLICATIONS: Locally injected 2-AG and URB602 decreased pain behaviour in a dose-dependent manner in an inflammatory model of pain. The antinociceptive effect of 2-AG was mediated by the CB(2) receptor.

Analgesics, Non-Narcotic↗

PubMed2005

Evidence for the involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation in mouse ear.

2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors. Two types of cannabinoid receptors have been identified to date. The CB1 receptor is abundantly expressed in the brain, and assumed to be involved in the attenuation of neurotransmission. On the other hand, the physiological roles of the CB2 receptor, mainly expressed in several types of inflammatory cells and immunocompetent cells, have not yet been fully elucidated. In this study, we investigated possible pathophysiological roles of the CB2 receptor and 2-arachidonoylglycerol in acute inflammation in mouse ear induced by the topical application of 12-O-tetradecanoylphorbol-13-acetate. We found that the amount of 2-arachidonoylglycerol was markedly augmented in inflamed mouse ear. In contrast, the amount of anandamide, another endogenous cannabinoid receptor ligand, did not change markedly. Importantly, 12-O-tetradecanoylphorbol-13-acetate-induced ear swelling was blocked by treatment with SR144528, a CB2 receptor antagonist, suggesting that the CB2 receptor is involved in the swelling. On the other hand, the application of AM251, a CB1 receptor antagonist, exerted only a weak suppressive effect. The application of SR144528 also reduced the 12-O-tetradecanoylphorbol-13-acetate-induced production of leukotriene B(4) and the infiltration of neutrophils in the mouse ear. Interestingly, the application of 2-arachidonoylglycerol to the mouse ear evoked swelling, which was abolished by treatment with SR144528. Nitric oxide was suggested to be involved in the ear swelling induced by 2-arachidonoylglycerol. These results suggest that the CB2 receptor and 2-arachidonoylglycerol play crucial stimulative roles during the course of inflammatory reactions.

Administration, Topical↗

PubMed2000

Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells.

We examined the effect of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca(2+) concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-arachidonoylglycerol induces a rapid transient increase in intracellular free Ca(2+) concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca(2+) transient induced by 2-arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. G(i) or G(o) is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system.

Amides↗