A Glial Endogenous Cannabinoid System Is Upregulated in the Brains of Macaques with Simian Immunodeficiency Virus-Induced Encephalitis

Benito, Cristina; Kim, Woong‐Ki; Chavarría, Iván; Hillard, Ceceila J; Mackie, Ken; Tolón, Rosa M.; Williams, Kenneth C.; Romero, Julián

doi:10.1523/jneurosci.3923-04.2005

Cited by 145 publications

(115 citation statements)

References 43 publications

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“…Vectashield mounting medium was purchased from Vector Laboratories (Burlingame, CA). The anti-N-terminal human CB 2 antibody was previously characterized (Benito et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

Functional Selectivity in CB₂ Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB₂ Ligands

Atwood

Wager‐Miller²,

Haskins³

et al. 2011

Mol Pharmacol

128

142

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Receptor internalization increases the flexibility and scope of G protein-coupled receptor (GPCR) signaling. CB 1 and CB 2 cannabinoid receptors undergo internalization after sustained exposure to agonists. However, it is not known whether different agonists internalize CB 2 to different extents. Because CB 2 is a promising therapeutic target, understanding its trafficking in response to different agonists is necessary for a complete understanding of its biology. Here we profile a number of cannabinoid receptor ligands and provide evidence for marked functional selectivity of cannabinoid receptor internalization. Classic, aminoalkylindole, bicyclic, cannabilactone, iminothiazole cannabinoid, and endocannabinoid ligands varied greatly in their effects on CB 1 and CB 2 trafficking. Our most striking finding was that (R)-(ϩ)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone (WIN55,212-2) (and other aminoalkylindoles) failed to promote CB 2 receptor internalization, whereas 5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol (CP55,940) robustly internalized CB 2 receptors. Furthermore, WIN55,212-2 competitively antagonized CP55,940-induced CB 2 internalization. Despite these differences in internalization, both compounds activated CB 2 receptors as measured by extracellular signal-regulated kinase 1/2 phosphorylation and recruitment of ␤-arrestin 2 to the membrane. In contrast, whereas CP55,940 inhibited voltage-gated calcium channels via CB 2 receptor activation, WIN55,212-2 was ineffective on its own and antagonized the effects of CP55,940. On the basis of the differences we found between these two ligands, we also tested the effects of other cannabinoids on these signaling pathways and found additional evidence for functional selectivity of CB 2 ligands. These novel data highlight that WIN55,212-2 and other cannabinoids show strong functional selectivity at CB 2 receptors and suggest that different classes of CB 2 ligands may produce diverse physiological effects, emphasizing that each class needs to be separately evaluated for therapeutic efficacy.

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“…Vectashield mounting medium was purchased from Vector Laboratories (Burlingame, CA). The anti-N-terminal human CB 2 antibody was previously characterized (Benito et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

Functional Selectivity in CB₂ Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB₂ Ligands

Atwood

Wager‐Miller²,

Haskins³

et al. 2011

Mol Pharmacol

128

142

View full text Add to dashboard Cite

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“…The protocol was used as described previously [11,12] with slight modifications. Tissue sections were deparaffinised and washed extensively in 50 m M potassium phosphate-buffered saline (KPBS; pH 8).…”

Section: Methodsmentioning

confidence: 99%

Endocannabinoid-Hydrolysing Enzymes in the Post-Mortem Cerebellum of Humans Affected by Hereditary Autosomal Dominant Ataxias

Rodríguez‐Cueto

Benito²,

Romero³

et al. 2014

Pathobiology

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Objectives: Spinocerebellar ataxias (SCAs) are characterized by a loss of balance and motor coordination due to degeneration of the cerebellum and its afferent and efferent connections. We recently found important changes in cannabinoid CB₁ and CB₂ receptors in the post-mortem cerebellum of patients affected by different SCAs. Methods: We wanted to further explore this issue by analysing the two major endocannabinoid-hydrolysing enzymes, fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL), in the post-mortem cerebellum of SCA patients and control subjects. Results: Immunoreactivity for the FAAH and MAGL enzymes was found in the granular layer, in Purkinje cells, in neurons of the dentate nucleus and in areas of white matter in the cerebellum of patients at levels frequently notably higher than those in control subjects. Using double-labelling procedures, we found co-localization of FAAH and MAGL with calbindin, supporting the presence of these enzymes in Purkinje neurons. Conclusions: Degradative endocannabinoid enzymes are significantly increased in the cerebellum of SCA patients, which would presumably lead to reduced endocannabinoid levels. The identification of these enzymes in Purkinje neurons suggests a relationship with the pathogenesis of SCAs and suggests that the endocannabinoid system could provide potential therapeutic targets for the treatment of disease progression in SCAs.

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“…The protocol used was as described previously (Tsou et al, 1998;Benito et al, 2003Benito et al, , 2005, with slight modifications. Tissue sections were deparaffinized and washed extensively in 50 mM potassium-PBS (KPBS).…”

Section: Methodsmentioning

confidence: 99%

Cannabinoid CB₁and CB₂Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

Benito¹,

Romero²,

Tolón³

et al. 2007

J. Neurosci.

Self Cite

241

175

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Increasing evidence supports the idea of a beneficial effect of cannabinoid compounds for the treatment of multiple sclerosis (MS).However, most experimental data come from animal models of MS. We investigated the status of cannabinoid CB 1 and CB 2 receptors and fatty acid amide hydrolase (FAAH) enzyme in brain tissue samples obtained from MS patients. Areas of demyelination were identified and classified as active, chronic, and inactive plaques. CB 1 and CB 2 receptors and FAAH densities and cellular sites of expression were examined using immunohistochemistry and immunofluorescence. In MS samples, cannabinoid CB 1 receptors were expressed by cortical neurons, oligodendrocytes, and also oligodendrocyte precursor cells, demonstrated using double immunofluorescence with antibodies against the CB 1 receptor with antibodies against type 2 microtubule-associated protein, myelin basic protein, and the platelet-derived growth factor receptor-␣, respectively. CB 1 receptors were also present in macrophages and infiltrated T-lymphocytes. Conversely, CB 2 receptors were present in T-lymphocytes, astrocytes, and perivascular and reactive microglia (major histocompatibility complex class-II positive) in MS plaques. Specifically, CB 2 -positive microglial cells were evenly distributed within active plaques but were located in the periphery of chronic active plaques. FAAH expression was restricted to neurons and hypertrophic astrocytes. As seen for other neuroinflammatory conditions, selective glial expression of cannabinoid CB 1 and CB 2 receptors and FAAH enzyme is induced in MS, thus supporting a role for the endocannabinoid system in the pathogenesis and/or evolution of this disease.

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A Glial Endogenous Cannabinoid System Is Upregulated in the Brains of Macaques with Simian Immunodeficiency Virus-Induced Encephalitis

Cited by 145 publications

References 43 publications

Functional Selectivity in CB₂ Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB₂ Ligands

Functional Selectivity in CB₂ Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB₂ Ligands

Endocannabinoid-Hydrolysing Enzymes in the Post-Mortem Cerebellum of Humans Affected by Hereditary Autosomal Dominant Ataxias

Cannabinoid CB₁and CB₂Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

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A Glial Endogenous Cannabinoid System Is Upregulated in the Brains of Macaques with Simian Immunodeficiency Virus-Induced Encephalitis

Cited by 145 publications

References 43 publications

Functional Selectivity in CB2 Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB2 Ligands

Functional Selectivity in CB2 Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB2 Ligands

Endocannabinoid-Hydrolysing Enzymes in the Post-Mortem Cerebellum of Humans Affected by Hereditary Autosomal Dominant Ataxias

Cannabinoid CB1and CB2Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

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Product

Resources

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Functional Selectivity in CB₂ Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB₂ Ligands

Functional Selectivity in CB₂ Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB₂ Ligands

Cannabinoid CB₁and CB₂Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis