Arachidonylcyclopropylamide increases microglial cell migration through cannabinoid CB 2 and abnormal-cannabidiol-sensitive receptors

Abstract

Microglial cells, the macrophages of the brain, express low, yet detectable levels of cannabinoid CB 1 receptors, which are known to modulate cell migration. To determine if cannabinoid CB 1 receptors expressed by microglial cells modulate their migration, we assessed whether arachidonylcyclopropylamide (ACPA, an agonist shown to selectively activate CB 1 receptors) affects the migration of BV-2 cells, a mouse microglial cell line. We found that ACPA induced a dose-dependent increase in BV-2 cell migration (EC 50=2.2 nM). This ACPA response was blocked by pertussis toxin pretreatment, suggesting the involvement of G i/o protein-coupled receptors. However, the cannabinoid CB 1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamidehydrochloride (SR141716A) did not prevent ACPA-induced BV-2 cell migration. Two antagonists of cannabinoid CB 2 receptors N-(1, S)-endo-1,3,3-trimethyl bicyclo(2,2,1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) and cannabinol, as well as two antagonists of the newly identified “abnormal-cannabidiol-sensitive” (abn-CBD) receptors (O-1918 and cannabidiol) prevented this response. Our results suggest that cannabinoid CB 2 receptors and abn-CBD receptors, rather than cannabinoid CB 1 receptors, regulate microglial cell migration, and that ACPA is a broad cannabinoid receptor agonist.