title: Nonpsychotropic cannabinoid receptors regulate microglial cell migration.
abstract: During neuroinflammation, activated microglial cells migrate toward dying neurons, where they exacerbate local cell damage. The signaling molecules that trigger microglial cell migration are poorly understood. In this paper, we show that pathological overstimulation of neurons by glutamate plus carbachol dramatically increases the production of the endocannabinoid 2-arachidonylglycerol (2-AG) but only slightly increases the production of anandamide and does not affect the production of two putative endocannabinoids, homo-gamma-linolenylethanolamide and docosatetraenylethanolamide. We further show that pathological stimulation of microglial cells with ATP also increases the production of 2-AG without affecting the amount of other endocannabinoids. Using a Boyden chamber assay, we provide evidence that 2-AG triggers microglial cell migration. This effect of 2-AG occurs through CB2 and abnormal-cannabidiol-sensitive receptors, with subsequent activation of the extracellular signal-regulated kinase 1/2 signal transduction pathway. It is important to note that cannabinol and cannabidiol, two nonpsychotropic ingredients present in the marijuana plant, prevent the 2-AG-induced cell migration by antagonizing the CB2 and abnormal-cannabidiol-sensitive receptors, respectively. Finally, we show that microglial cells express CB2 receptors at the leading edge of lamellipodia, which is consistent with the involvement of microglial cells in cell migration. Our study identifies a cannabinoid signaling system regulating microglial cell migration. Because this signaling system is likely to be involved in recruiting microglial cells toward dying neurons, we propose that cannabinol and cannabidiol are promising nonpsychotropic therapeutics to prevent the recruitment of these cells at neuroinflammatory lesion sites.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Walter
authors.forename: Allyn
authors.initials: A
authors.lastname: Franklin
authors.forename: Anke
authors.initials: A
authors.lastname: Witting
authors.forename: Christian
authors.initials: C
authors.lastname: Wade
authors.forename: Yiheng
authors.initials: Y
authors.lastname: Xie
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Nephi
authors.initials: N
authors.lastname: Stella
mesh_terms: D000818:Animals; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D005989:Glycerides / Q000096:biosynthesis; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000145:classification / Q000235:genetics / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated; D005989:Glycerides; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D018698:Glutamic Acid; C094503:glyceryl 2-arachidonate; D002217:Carbachol; D020928:Mitogen-Activated Protein Kinases