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PubMed2003

Differential roles of CB1 and CB2 cannabinoid receptors in mast cells.

Cannabinoid modulation of immune responses is a pathological consequence of marijuana abuse and a potential outcome of therapeutic application of the drug. Moreover, endogenous cannabinoids are physiological immune regulators. In the present report, we describe alterations in gene transcription that occur after cannabinoid exposure in a mast cell line, RBL2H3. Cannabinoid exposure causes marked changes in the transcript levels for numerous genes, acting both independently of and in concert with immunoreceptor stimulation via Fc epsilon RI. In two mast cell lines, we observed mRNA and protein expression corresponding to both CB1 and CB2 cannabinoid receptor isoforms, contrary to the prevailing view that CB1 is restricted to the CNS. We show that coexpression of the two isoforms is not functionally redundant in mast cells. Analysis of signaling pathways downstream of cannabinoid application reveals that activation of extracellular signal-regulated kinase, AKT, and a selected subset of AKT targets is accomplished by CB2 ligands and nonselective CB1/CB2 agonists in mast cells. CB1 inhibition does not affect AKT or extracellular signal-regulated kinase activation by cannabinoids, indicating that CB2 is the predominant regulatory receptor for these kinases in this cell context. CB1 receptors are, however, functional in these mast cells, since they can contribute to suppression of secretory responses.

Animals↗

PubMed2002

Cloning and molecular characterization of the rat CB2 cannabinoid receptor.

The rat peripheral cannabinoid receptor (rCB2) was cloned from a Sprague-Dawley rat spleen cDNA library and when translated, encodes a protein of 410 amino acids. Alignment of rCB2 with mouse (mCB2) and human (hCB2) peripheral cannabinoid receptors reveals a high degree of homology except in the carboxy terminus where rCB2 is 50 and 63 residues longer than hCB2 and mCB2, respectively. PCR screening and sequencing of rat genomic DNA showed that rCB2 is encoded by three exons interrupted by two introns, one of which is polymorphic and contains a 209 base pair B2 (SINE) element. By Northern hybridization and ribonuclease protection assay (RPA), rCB2 mRNA was detected in rat spleen, testis, thymus and lung but not in rat brain, heart, kidney or liver. Like hCB2 and mCB2 receptors, rCB2 activates mitogen-activated protein kinase when it is stably expressed in Chinese Hamster Ovary (CHO) cells. The importance of the carboxy terminus in regulating CB2 receptor desensitization and internalization is well-established. Thus, the profound differences identified in this region of the CB2 receptor between species mandates caution when extrapolating experimental results from non-human models to the effects of chronic CB2 receptor stimulation in humans.

Amino Acid Sequence↗

PubMed2005

Antifibrogenic role of the cannabinoid receptor CB2 in the liver.

BACKGROUND & AIMS: Hepatic myofibroblasts are central for the development of liver fibrosis associated with chronic liver diseases, and blocking their accumulation may prevent fibrogenesis. Cannabinoids are the active components of marijuana and act via 2 G-protein-coupled receptors, CB1 and CB2. Here, we investigated whether liver fibrogenic cells are a target of cannabinoids. METHODS: CB2 receptors were characterized in biopsy specimens of normal human liver and active cirrhosis by immunohistochemistry, and in cultures of hepatic stellate cells and hepatic myofibroblasts by reverse-transcription polymerase chain reaction (RT-PCR), immunocytochemistry, and GTPgammaS assays. Functional studies were performed in cultured hepatic myofibroblasts and activated hepatic stellate cells. Carbon tetrachloride-induced liver fibrosis was studied in mice invalidated for CB2 receptors. RESULTS: In liver biopsy specimens from patients with active cirrhosis of various etiologies, CB2 receptors were expressed in nonparenchymal cells located within and at the edge of fibrous septa in smooth muscle alpha-actin-positive cells. In contrast, CB2 receptors were not detected in normal human liver. CB2 receptors were also detected in cultured hepatic myofibroblasts and in activated hepatic stellate cells. Their activation triggered potent antifibrogenic effects, namely, growth inhibition and apoptosis. Growth inhibition involved cyclooxygenase-2, and apoptosis resulted from oxidative stress. Finally, mice invalidated for CB2 receptors developed enhanced liver fibrosis following chronic carbon tetrachloride treatment as compared with wild-type mice. CONCLUSIONS: These data constitute the first demonstration that CB2 receptors are highly up-regulated in the cirrhotic liver, predominantly in hepatic fibrogenic cells. Moreover, this study also highlights the antifibrogenic role of CB2 receptors during chronic liver injury.

Adult↗

PubMed2006

CB2 cannabinoid receptor mediation of antinociception.

Management of acute pain remains a significant clinical problem. In preclinical studies, CB2 cannabinoid receptor-selective agonists inhibit nociception without producing central nervous system side effects. The CB2 receptor-selective agonist AM1241 produces antinociceptive effects that are antagonized by CB2, but not CB1, receptor-selective antagonists, suggesting that activation of CB2 receptors results in antinociception. However, it has not been possible to definitively demonstrate that these effects are mediated by CB2 receptors, because we have lacked the pharmacological tools to confirm the in vivo receptor selectivity of the antagonists used. Further, recent evidence for cannabinoid-like receptors beyond CB1 and CB2 raises the possibility that AM1241 exerts its antinociceptive effects at uncharacterized CB2-like receptors that are also inhibited by AM630. The experiments reported here further test the hypothesis that CB2 receptor activation inhibits nociception. They evaluated the antinociceptive actions of AM1241 and the less-selective CB2 receptor agonist WIN55,212-2 in wild-type (CB2+/+) mice and in mice with genetic disruption of the CB2 receptor (CB2-/- mice). AM1241 inhibited thermal nociception in CB2+/+ mice, but had no effect in CB2-/- littermates. WIN55,212-2 produced equivalent antinociception in CB1+/+ and CB1-/- mice, while its antinociceptive effects were reduced in CB2-/- compared to CB2+/+ mice. The effects of morphine were not altered in CB2-/- compared to CB2+/+ mice. These data strongly suggest that AM1241 produces antinociception in vivo by activating CB2 cannabinoid receptors. Further, they confirm the potential therapeutic relevance of CB2 cannabinoid receptors for the treatment of acute pain.

Analgesics↗

PubMed2004

Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naïve rats and in rat models of inflammatory and neuropathic pain.

Peripheral cannabinoid 2 receptors (CB2 receptors) modulate immune responses and attenuate nociceptive behaviour in models of acute and persistent pain. The aim of the present study was to investigate whether peripheral CB2 receptors modulate spinal processing of innocuous and noxious responses and to determine whether there are altered roles of CB2 receptors in models of persistent pain. Effects of local administration of the CB2 receptor agonist JWH-133 (5 and 15 microg/50 microL) on mechanically evoked responses of spinal wide dynamic range (WDR) neurons in noninflamed rats, rats with carrageenan-induced hindpaw inflammation, sham operated rats and spinal nerve-ligated (SNL) rats were determined in anaesthetized rats in vivo. Mechanical stimulation (von Frey filaments, 6-80 g) of the peripheral receptive field evoked firing of WDR neurons. Mechanically evoked responses of WDR neurons were similar in noninflamed, carrageenan-inflamed, sham-operated and SNL rats. Intraplantar injection of JWH-133 (15 microg), but not vehicle, significantly (P < 0.05) inhibited innocuous and noxious mechanically evoked responses of WDR neurons in all four groups of rats. In many cases the selective CB2 receptor antagonist, SR144528 (10 microg/50 microL), attenuated the inhibitory effects of JWH-133 (15 microg) on mechanically evoked WDR neuronal responses. The CB1 receptor antagonist, SR141716A, did not attenuate the inhibitory effects of JWH-133 on these responses. Intraplantar preadministration of JWH-133 also inhibited (P < 0.05) carrageenan-induced expansion of peripheral receptive fields of WDR dorsal horn neurons. This study demonstrates that activation of peripheral CB2 receptors attenuates both innocuous- and noxious-evoked responses of WDR neurons in models of acute, inflammatory and neuropathic pain.

Action Potentials↗

PubMed2002

The cytoplasmic helix of cannabinoid receptor CB2, a conformational study by circular dichroism and (1)H NMR spectroscopy in aqueous and membrane-like environments.

The cytoplasmic helix domain (fourth cytoplasmic loop, helix 8) of numerous G protein-coupled receptors (GPCRs) such as rhodopsin and the beta-adrenergic receptor exhibit unique structural and functional characteristics. Computer models also predict this structure for the cannabinoid CB2 receptor, another member of the GPCR superfamily. In our study, a peptide corresponding to helix 8 of the CB2 receptor was synthesized chemically and its secondary structure determined by circular dichroism (CD) and (1)H NMR spectroscopy. NMR and CD revealed an alpha-helical structure in this region in both dodecylphosphocholine micelles and dimethylsulfoxide, in contrast to a random coil configuration found in aqueous solvent. This finding is in good agreement with other previous GPCR structural studies including X-ray crystallography. By combining our finding with other studies, we further hypothesize that the amphipathic nature of helix 8 can play a significant role in the function and regulation of CB receptors as well as other GPCRs in general.

Circular Dichroism↗

PubMed2005

CB2 cannabinoid receptors in trabecular meshwork cells mediate JWH015-induced enhancement of aqueous humor outflow facility.

PURPOSE: To study the effects of JWH015, a CB2-selective agonist, on aqueous humor outflow facility, to investigate whether functional CB2 cannabinoid receptors are expressed in trabecular meshwork cells, and to study whether these receptors are involved in the enhancement of outflow facility induced by JWH015. METHODS: A porcine anterior segment perfused organ culture model was used to measure the effects of JWH015 on aqueous humor outflow facility. Immunofluorescence microscopy, Western blot analysis, and mitogen-activated protein (MAP) kinase activity assays were used to study the expression of CB2 cannabinoid receptors on cultured porcine trabecular meshwork cells and the coupling of these receptors to p42/44 MAP kinase. RESULTS: The outflow facility was increased dose dependently within 1 hour after adding 10, 30, and 100 nM of JWH015, a CB2 agonist. In addition, the effect of 100 nM of JWH015 was completely blocked by SR144528, a selective CB2 antagonist. Furthermore, the outflow-enhancing effect of JWH015 was blocked by pretreatment with PD98059, an inhibitor of the p42/44 MAP kinase pathway. In immunofluorescence microscopy and Western blot studies, positive signals were detected on cultured porcine trabecular meshwork cells with an anti-CB2 antibody. In MAP kinase assays, treatment of porcine trabecular meshwork cells with 100 nM of JWH015 activated p42/44 MAP kinase activity. Pretreatment with SR144528 blocked the effect of JWH015 on p42/44 MAP kinase activity. CONCLUSIONS: The data from this study demonstrate that the CB2-selective cannabinoid agonist JWH015 increases aqueous humor outflow facility. The results also indicate that functional CB2 cannabinoid receptors are expressed in trabecular meshwork cells, and these receptors are involved in the enhancement of outflow facility induced by JWH015.

Animals↗

PubMed2003

3D structural model of the G-protein-coupled cannabinoid CB2 receptor.

The potential for therapeutic specificity in regulating diseases and for reduced side effects has made cannabinoid (CB) receptors one of the most important G-protein-coupled receptor (GPCR) targets for drug discovery. The cannabinoid (CB) receptor subtype CB2 is of particular interest due to its involvement in signal transduction in the immune system and its increased characterization by mutational and other studies. However, our understanding of their mode of action has been limited by the absence of an experimental receptor structure. In this study, we have developed a 3D model of the CB2 receptor based on the recent crystal structure of a related GPCR, bovine rhodopsin. The model was developed using multiple sequence alignment of homologous receptor sub-types in humans and mammals, and compared with other GPCRs. Alignments were analyzed with mutation scores, pairwise hydrophobicity profiles and Kyte-Doolittle plots. The 3D model of the transmembrane segment was generated by mapping the CB2 sequence onto the homologous residues of the rhodopsin structure. The extra- and intracellular loop regions of the CB2 were generated by searching for homologous C(alpha) backbone sequences in published structures in the Brookhaven Protein Databank (PDB). Residue side chains were positioned through a combination of rotamer library searches, simulated annealing and minimization. Intermediate models of the 7TM helix bundles were analyzed in terms of helix tilt angles, hydrogen-bond networks, conserved residues and motifs, possible disulfide bonds. The amphipathic cytoplasmic helix domain was also correlated with biological and site-directed mutagenesis data. Finally, the model receptor-binding cavity was characterized using solvent-accessible surface approach.

Amino Acid Sequence↗

PubMed2006

Synthesis and pharmacology of 11-nor-1-methoxy-9-hydroxyhexahydrocannabinols and 11-nor-1-deoxy-9-hydroxyhexahydrocannabinols: new selective ligands for the cannabinoid CB2 receptor.

Fourteen novel CB2 receptor selective cannabinoids were synthesized via initial Lewis acid catalyzed rearrangement of resorcinol precursors to obtain the cannabinoid moiety. These are the 1-methoxy-9-hydroxyhexahydrocannabinols and the 1-deoxy-9-hydroxyhexahydrocannabinols, with 1',1'-dimethylalkyl side chains of four to seven carbon atoms at C-3 of the cannabinoid nucleus. The cannabinols synthesized and described in this paper all exhibit greater affinity for the CB2 receptor than for the CB1 receptor. Exceptionally high CB2 affinity was observed for 1-deoxy-9beta-hydroxy-dimethylhexylhexahydrocannabinol (JWH-361, 9, n = 3) K(i) = 2.7 nM and 1-deoxy-9beta-hydroxydimethylpentylhexahydrocannabinol (JWH-300, 9, n = 2) K(i) = 5.3 nM. In general, the stereochemistry of the 9-hydroxy group is important and the beta-orientation enhances both CB2 receptor affinity and selectivity.

Cannabinol↗

PubMed2004

Purification and mass spectroscopic analysis of human CB2 cannabinoid receptor expressed in the baculovirus system.

The cannabinergic system is present in a variety of organs and tissues that perform a wide range of essential physiologic functions making it an inherently important therapeutic target for drug discovery. In order to augment our knowledge regarding the interactions between cannabinoid receptors (CBs) and their ligands, efficient and effective tools are essential for robust expression and purification of these membrane-bound proteins. In this report, we describe a suitable method for purification of the human cannabinoid receptor 2 (CB2) to a qualitative and quantitative level sufficient for mass spectral analysis. We utilized a baculovirus expression system, incorporating several epitope tags to facilitate purification and to ameliorate the effect the tags have on CB2 expression and function. Expressed protein encoded by a carboxy (C)-terminal His-tagged CB2 construct displayed a B(max) value of 9.3 pmol/mg with a K(D) of 7.30 nM using [3(H)]CP-55(940), a standard cannabinoid radioligand, and was selected for subsequent purification experiments. Western blot analysis of purified membrane protein yielded several forms of CB2, the most abundant being a 41 kDa peptide. A second protein species was observed with an apparent molecular weight of 46 kDa representing a glycosylated form of CB2. In addition, a CB2 homodimer was also identified. The purified receptor was subjected to mass spectroscopic analysis to confirm its identity and purity. Mass spectra corresponding to the intracellular, extracellular and transmembrane domains were obtained. These experiments exemplify the importance of high-level expression systems when developing membrane-bound protein purification strategies. This work will aid in the identification of receptor-ligand binding sites, the characterization of molecular features involved in receptor activation, and the elucidation of the CB2 receptor tertiary structure.

Amino Acid Sequence↗

PubMed2001

In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor.

JTE-907 [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] was evaluated in vitro and in vivo as a novel selective ligand for cannabinoid receptor of peripheral type (CB2). The compound binds with high affinity to human CB2 or mouse CB2 expressed on CHO cell membrane and to rat CB2 on splenocytes. The K(i) affinities for human, mouse, and rat CB2 were 35.9, 1.55, and 0.38 nM, respectively. The selectivity ratio for the CB2 receptors compared with central nervous type receptors (CB1) of human (expressed on CHO cells), and mouse and rat CB1 on cerebellum were 66, 684, and 2760, respectively. JTE-907 showed concentration-dependent increase of forskolin-stimulated cAMP production in CHO cells expressing human and mouse CB2 in vitro, i.e., JTE-907 behaved as an inverse agonist, which is in contrast to Win55212-2 that reduces cAMP as an agonist. JTE-907 dosed orally inhibited carrageenin-induced mouse paw edema dose dependently. The same in vivo effect was observed with other cannabinoid receptor ligands such as SR144528, Delta(9)-tetrahydrocannabinol (THC), and Win55212-2. This is the first report that a CB2-selective inverse agonist, JTE-907, has an anti-inflammatory effect in vivo, and how the inverse agonist showed the same effect as Win55212-2 and Delta(9)-THC is discussed.

Analgesics↗

PubMed2006

Methods to study the behavioral effects and expression of CB2 cannabinoid receptor and its gene transcripts in the chronic mild stress model of depression.

Behavioral and molecular methods were used to study and determine whether there is a link between depression that may be a factor in drug/alcohol addiction, and the endocannabinoid hypothesis of substance abuse. Depression is a lack of interest in the pleasurable things of life (termed anhedonia) and depressed mood. It is unknown whether CB2 cannabinoid receptors are expressed in the brain and whether they are involved in depression and substance abuse. Therefore, mice were subjected daily for 4 wk to chronic mild stress (CMS), and anhedonia was measured by the consumption of 2% sucrose solution. Behavioral and rewarding effects of abused substances were determined in the CMS and control animals. The expression of CB2 receptors and their gene transcripts was compared in the brains of CMS and control animals by Western blotting using CB2 receptor antibody and reverse transcriptase-polymerase chain reaction (RT-PCR). Furthermore, the expression and immunocytochemical identification of CB2 cannabinoid receptor in the rat brain were determined. CMS induced gender-specific aversions, which were blocked by WIN55,212-2, a nonspecific CB1 and CB2 cannabinoid receptor agonist. Direct CB2 antisense oligonucleotide microinjection into the mouse brain induced anxiolysis, indicating that CB2 or CB2-like receptors are present in the brain and may influence behavior. The major finding from these studies was the expression of CB2 receptor and its gene transcript in the mouse brain, which was enhanced by CMS. These preliminary results, if confirmed, suggest that the CB2 receptors are expressed in the mammalian brain and may be involved in depression and substance abuse.

Animals↗

PubMed2005

CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids.

CB(2) cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB(2) receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB(2) receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB(2) receptor-mediated inhibition of pain responses. Here, we test the hypothesis that CB(2) receptor activation stimulates release from keratinocytes of the endogenous opioid beta-endorphin, which then acts at opioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB(2) receptor-selective agonist AM1241 were prevented in rats when naloxone or antiserum to beta-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that beta-endorphin is necessary for CB(2) receptor-mediated antinociception. Further, AM1241 did not inhibit nociception in mu-opioid receptor-deficient mice. Hindpaw injection of beta-endorphin was sufficient to produce antinociception. AM1241 stimulated beta-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB(2) cannabinoid receptor-selective antagonist and was not observed in skin from CB(2) cannabinoid receptor-deficient mice. These data suggest that CB(2) receptor activation stimulates release from keratinocytes of beta-endorphin, which acts at local neuronal mu-opioid receptors to inhibit nociception. Supporting this possibility, CB(2) immunolabeling was detected on beta-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of beta-endorphin, where CB(2) receptors are present, leading to anatomical specificity of opioid effects.

Analgesics↗

PubMed2004

Expression, purification, and isotope labeling of cannabinoid CB2 receptor fragment, CB2(180-233).

To develop an approach to obtain milligram quantities of purified isotope-labeled seven transmembrane G-protein coupled cannabinoid (CB) receptor for NMR structural analysis, we chose a truncated CB receptor fragment, CB2(180-233), spanning from the fifth transmembrane domain (TM5) to the associated loop regions of cannabinoid CB2 receptor. This highly hydrophobic membrane protein fragment was pursued for developmental studies of membrane proteins through expression and purification in Escherichia coli. The target peptide was cloned and over-expressed in a preparative scale as a fusion protein with a modified TrpDeltaLE1413 (TrpLE) leader sequence and a nine-histidine tag at its N-terminal. An experimental protocol for enzyme cleavage was developed by using Factor Xa to remove the TrpLE tag from the fusion protein. A purification process was also established using a nickel affinity column and reverse-phase HPLC, and then monitored by SDS-PAGE and MS. This expression level is one of the highest reported for a G-protein coupled receptor and fragments in E. Coli, and provided a sufficient amount of purified protein for further biophysical studies.

Chromatography, High Pressure Liquid↗

PubMed2006

Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans.

We tested if cannabinoid type 2 receptor (CB2) in the central nervous system plays a role in alcohol abuse/dependence in animal model and then examined an association between the CB2 gene polymorphism and alcoholism in human. Mice experiencing more alcohol preference by drinking showed reduced Cb2 gene expression, whereas mice with little preference showed no changes of it in ventral midbrain. Alcohol preference in conjunction with chronic mild stress were enhanced in mice treated with CB2 agonist JWH015 when subjected to chronic stress, whereas antagonist AM630 prevented development of alcohol preference. There is an association between the Q63R polymorphism of the CB2 gene and alcoholism in a Japanese population (P=0.007; odds ratio 1.25, 95% CI, (1.06-1.47)). CB2 under such environment is associated with the physiologic effects of alcohol and CB2 antagonists may have potential as therapies for alcoholism.

Adult↗

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

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↗