Δ-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two main cannabinoid constituents of marijuana and hashish. The pharmacology of Δ-THC has been extensively studied, whereas our understanding of the pharmacology of CBD has remained limited, despite excitement in CBD's potential role in treating certain pediatric epilepsies and its reputation for attenuating some Δ-THC-induced effects. It was established early on that CBD binds poorly to the orthosteric site of CB or CB cannabinoid receptors, and its actions were commonly attributed to other noncannabinoid receptor mechanisms. However, recent evidence suggests that CBD does indeed act at cannabinoid CB receptors as a negative allosteric modulator (NAM) of CB signaling. By altering the orthosteric signaling of a G protein-coupled receptor, allosteric modulators greatly increase the richness of G protein-coupled receptor pharmacology. We have recently surveyed candidate CB NAMs in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and have now tested CBD in this model. We find that although CBD has no direct effect on excitatory transmission, it does inhibit two forms of endogenous cannabinoid-mediated retrograde synaptic plasticity: depolarization-induced suppression of excitation and metabotropic suppression of excitation, while not affecting signaling via GABA-B receptors. These results are consistent with the recently described NAM activity of CBD and suggest interesting possible mechanisms for CBD's therapeutic actions.

Many diseases of the nervous system are accompanied by alterations in synaptic functions. Synaptic plasticity mediated by the endogenous cannabinoid system involves the activation of the cannabinoid receptor 1 (CB1R). The principles of CB1R signaling must be understood in detail for its therapeutic exploration. We detected the Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1) as a novel CB1R partner. SGIP1 is functionally linked to clathrin-mediated endocytosis and its overexpression in animals leads to an energy regulation imbalance resulting in obesity. We report that SGIP1 prevents the endocytosis of activated CB1R and that it alters signaling via the CB1R in a biased manner. CB1R mediated G-protein activation is selectively influenced by SGIP1, β-arrestin associated signaling is changed profoundly, most likely as a consequence of the prevention of the receptor's internalization elicited by SGIP1.

SGIP1 is involved in regulation of emotionality, mood, and nociception and tunes in vivo signaling of Cannabinoid Receptor 1