When orexins meet cannabinoids: Bidirectional functional interactions

A growing body of evidence suggests the existence of biochemical and functional interactions between the endocannabinoid and orexin systems. Cannabinoid and orexin receptors have been shown to form heterodimers in agreement with the overlapping distribution of both receptors in several brain areas, and the activation of common intracellular signaling pathways, such as the MAP kinase cascade. The activation of orexin receptors induces the synthesis of the endocannabinoid 2-arachidonoyl glycerol suggesting that the endocannabinoid system participates in some physiological functions of orexins. Indeed, functional interactions between these two systems have been demonstrated in several behavioral responses including nociception, reward and food intake. The present review is focused on the latest developments in cannabinoid-orexin cross-modulation and the implications of this interesting interaction.This work was supported by Instituto de Salud Carlos III (PI14/00210),the Fundació la Marató de TV3 (231/C/2014) to PR,“Plan Nacional sobre Drogas”(#2014I019) and “Ministerio de Economía y Competitividad”(SAF2017-85299-R) to FB, and the Catalunya Government AGAUR (2017SGR210). We would like to thank Carla Ramón Duaso for her help with reference editing