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.
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