Endocannabinoid signaling in microglial cells

doi:10.1016/j.neuropharm.2008.07.037

Neuropharmacology

Volume 56, Supplement 1, 2009, Pages 244-253

https://doi.org/10.1016/j.neuropharm.2008.07.037 Get rights and content

Abstract

The endocannabinoid signaling system (eCBSS) is composed of cannabinoid (CB) receptors, their endogenous ligands (the endocannabinoids, eCB) and the enzymes that produce and inactivate these ligands. Neurons use this signaling system to communicate with each other and Δ⁹-tetrahydrocannabinol (THC), the main psychotropic ingredient of Cannabis sativa, induces profound behavioral effects by impinging on this communication. Evidence now shows that microglia, the macrophages of the brain, also express a functional eCBSS and that activation of CB receptors expressed by activated microglia controls their immune-related functions. This review summarizes this evidence, discusses how microglia might use the eCBSS to communicate with each other and neighboring cells, and argues that compounds selectively targeting the eCBSS expressed by microglia constitute valuable therapeutics to manage acute and chronic neuroinflammation, without inducing the psychotropic effects and underlying addictive properties commonly associated with THC.

Section snippets

Cannabinoid receptors

At least five subtypes of CB receptors have been identified: the two cloned receptors (CB₁ and CB₂), GPR55, and two receptors that have been pharmacologically pinpointed but remain to be identified at the molecular level.

CB₁ receptors are expressed throughout the brain by many different subtypes of neurons and at lower levels by other types of cells (Howlett et al., 2002, Matsuda et al., 1990, Tsou et al., 1998). In brain, they are most abundant in GABAergic interneurons, being between three

Endocannabinoid production, pharmacology and inactivation

In 1992, Raphael Mechoulam and coworkers identified arachidonoylethanolamide, which was named anandamide, as the first endogenous compound that binds to CB₁ receptors with high affinity (Devane et al., 1992). Anandamide is considered a bona fide eCB because (I) it is produced by cells in an activity-dependent manner, (II) it activates CB₁ and CB₂ receptors and (III) it is enzymatically inactivated. Depolarization- and agonist-induced increase in anandamide production was initially shown in

Microglial cells

Microglia derive from the monocytic lineage, entering the developing brain before the establishment of a functional blood–brain barrier and distribute uniformly throughout the parenchyma (Streit, 2001). In healthy brain, microglia display a “resting” phenotype responsible for the continuous immune surveillance of their environment (Fetler and Amigorena, 2005, Raivich, 2005). Studies carried out with GFP-expressing microglia suggest that thorough surveillance of the CNS environment is linked to

Microglial cells express functional cannabinoid receptors

Whether resting microglia found in healthy brain parenchyma express CB₁ and/or CB₂ receptors has not been addressed directly, but one can presume – as stated at the beginning of this review – that these cells do not express CB₂ receptors (because the mRNA encoding for these receptors is undetectable in healthy brain tissue) (Carlisle et al., 2002, Derocq et al., 1995, Galiègue et al., 1995, Griffin et al., 1999, McCoy et al., 1999, Munro et al., 1993, Schatz et al., 1997, Sugiura et al., 2000).

Microglial cells produce and inactivate endocannabinoids

Microglial cells in culture produce anandamide and 2-AG, with ionomycin and millimolar concentrations of ATP selectively increasing 2-AG production (Carrier et al., 2004, Walter et al., 2003). The molecular mechanism underlying ATP-induced 2-AG production involves the activation of P2X₇ ionotropic receptors, which are highly permeable to calcium and induce sustained rises in intracellular calcium that directly increase DGL activity while inhibiting MGL activity (Witting et al., 2004a). This

Conclusions

The studies outlined in this review were carried out over the last decade and convincingly show that microglia express many of the components required for functional eCB paracrine and autocrine signaling. Microglia express CB₂ receptors and non-psychotropic CB₂ agonists regulate their immune-related functions, including migration, proliferation and cytotoxin release. Microglia produce large amounts of eCBs that most likely contribute to the long-lasting increase in eCB levels measured under

Acknowledgments

To the members of my laboratory (Eiron Cudaback, Eric Horne, William Marrs, Aaron Miller, Poulami Mitra, Faith Reyes and Michelle Sexton) for critical reading of this manuscript, and to NIDA (DA 14486, DA21285 and DA22469) for grant support.

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ReviewEndocannabinoid signaling in microglial cells

Abstract

Section snippets

Cannabinoid receptors

Endocannabinoid production, pharmacology and inactivation

Microglial cells

Microglial cells express functional cannabinoid receptors

Microglial cells produce and inactivate endocannabinoids

Conclusions

Acknowledgments

The Journal of Biological Chemistry

Chemistry & Biology

Blood

International Immunopharmacology

Neuron

The Journal of Biological Chemistry

The Journal of Biological Chemistry

FEBS Letters

Neuron

European Journal of Pharmacology

Biochemical and Biophysical Research Communications

Brain Research

European Journal of Pharmacology

Neuropharmacology

Neuroscience

Neuroscience Letters

Journal of Biological Chemistry

Journal of Biological Chemistry

European Journal of Pharmacology

Biochemical Pharmacology

Archives of Biochemistry and Biophysics

Biochemical and Biophysical Research Communications

Neuropharmacology

Therapeutic action of cannabinoids in a murine model of multiple sclerosis

The Journal of Neuroscience

Endocannabinoids control spasticity in a multiple sclerosis model

The FASEB Journal

Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia

Glia

Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol

Neuropharmacology

A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis

The Journal of Neuroscience

Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaques-associated glia in Alzheimer's disease brains

The Journal of Neuroscience

Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis

The Journal of Neuroscience

CB1 receptor-mediated control of the release of endocannabinoids (as assessed by microdialysis coupled with LC/MS) in the rat hypothalamus

European Journal of Neuroscience

Massive accumulation of N-acylethanolamines after stroke. Cell signalling in acute cerebral ischemia?

Journal of Neurochemistry

Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice

The FASEB Journal

Activation of mitogen-activated protein kinase by stimulation of the central cannabinoid receptor CB1

Biochemical Journal

Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor

European Journal of Biochemistry

Evidence for a new G protein-coupled cannabinoid receptor in mouse brain

Molecular Pharmacology

Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration

The Journal of Neuroscience

Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats

Psychopharmacology (Berlin)

Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism

Molecular Pharmacology

Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw

Naunyn-Schmiedeberg's Archives of Pharmacology

BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Nature

Functional disassociation of the central and peripheral fatty acid amide signaling systems

Proceedings of the National Academy of Sciences of the United States of America

Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase

Proceedings of the National Academy of Sciences of the United States of America

ATP mediates rapid microglial response to local brain injury in vivo

Nature Neuroscience

Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus

The Journal of Neuroscience

Isolation and structure of a brain constituent that binds to the cannabinoid receptor

Science

Targeting the endocannabinoid system: to enhance or reduce?

Review
Endocannabinoid signaling in microglial cells

Cannabinoid CB₂ receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaques-associated glia in Alzheimer's disease brains

Cannabinoid CB₁ and CB₂ receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis

CB₁ receptor-mediated control of the release of endocannabinoids (as assessed by microdialysis coupled with LC/MS) in the rat hypothalamus

Activation of mitogen-activated protein kinase by stimulation of the central cannabinoid receptor CB₁

Signaling pathway associated with stimulation of CB₂ peripheral cannabinoid receptor

Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB₂ receptor-dependent mechanism