Evidence for a Cannabinoid Receptor in Immunomodulation by Cannabinoid Compounds

Abstract

A number of structurally related cannabinoid compounds, including the major psychoactive component of marihuana, delta-9-tetrahydrocannabinol (Δ⁹-THC), have been widely established as being immunosuppressive. Although much has been learned with respect to which immune responses demonstrate sensitivity to modulation by cannabinoids, the mechanism(s) responsible for these effects has remained elusive. Over the past decade, significant insight has been forthcoming regarding the cellular and biochemical mechanisms which mediate the effects of cannabinoids on the central nervous system (CNS). From these investigations at least three lines of evidence have emerged which strongly implicated a role by a cannabinoid receptor in CNS association cannabinoid activity and include: (i) stereoselective effects; (ii) a high degree of specific binding by the synthetic bicyclic cannabinoid, CP-55,940, to various brain tissue preparation as analyzed by radioligand binding; and (iii) cannabinoid modulation of adenylate cyclase-cAMP second messenger system. The existence of a cannabinoid receptor in association with neuronal tissue has been recently confirmed by Matsuda and coworkers (1) through the isolation and cloning of a G-protein coupled receptor from a rat brain cDNA library. When cloned, this receptor demonstrate all of the characteristics predicted for a putative cannabinoid receptor. More recently, an almost identical receptor has been cloned from human brain which possessed more than 97% homogeneity (2) to that isolated by Matsuda and coworkers. In light of these findings, the objective of the presently reported studies was to explore the possibility that immune inhibition by cannabimimetic agents is mediated through a cannabinoid receptor present on immunocytes.