Review links orexin and endocannabinoid signalling, but clinical value remains…

Orexinergic system is involved in conditions like narcolepsy, eating disorders, central and neuropathic pain where it is directly or indirectly contributing towards the development of symptoms of these conditions. Endocannabinoid system is present throughout the body and acts via cannabinoid (CB) receptors which have their own role in pain modulation, memory processing, movement and balance control. Evidence is growing that the two systems interact, both through receptor-level mechanisms and through orexin-driven synthesis of 2-arachidonoylglycerol (2-AG). CB1-OX1 heteromer formation has been demonstrated in heterologous cell systems, and OX1 antagonism has been reported to potentiate CB2 signalling in microglial models of Alzheimer's disease (AD), although the therapeutic value of orexin antagonism in AD remains unresolved. In rodent fear-extinction paradigms, orexin-A impairs extinction through a 2-AG-dependent mechanism involving microglial CB2 receptors in the basolateral amygdala. In rodent models of visceral pain, CB1 and CB2 antagonists block the visceral hyposensitivity induced by centrally administered orexin, indicating that endocannabinoid signalling is required for this effect. This review summarises the evidence for orexin-endocannabinoid interaction in AD, anxiety and visceral pain, and discusses translational implications, including the absence of approved drugs acting on both systems.