Cannabinoid receptor 2 (Cb2r) mediates cannabinol (CBN) induced developmental defects in zebrafish

Of the three primary cannabinoids in cannabis: Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), cannabidiol (CBD) and cannabinol (CBN), very little is known about the actions of CBN, the primary oxidative metabolite of THC. Our goal was to determine if CBN exposure during gastrulation alters embryonic development, and if so, does it act via the canonical cannabinoid receptors. Zebrafish embryos were exposed to CBN during gastrulation and exhibited dose-dependent malformations, increased mortality, decreased locomotion and a reduction in motor neuron branching. Moreover, larva showed a significant reduction in the response to sound stimuli. CBN exposure altered the development of hair cells associated with otic vesicles and the lateral line. Pharmacological block of Cb2rs with AM 630 or JTE 907 prevented many of the CBN-induced developmental defects, while block of Cb1rs with AM 251 or CP 945598 had little or no effect. Altogether we show that embryonic exposure to CBN results in alterations in embryonic growth, neuronal and hair cell development, physiology and behavior via Cb2r-mediated mechanisms.