Physiology of the orexinergic/hypocretinergic system: a revisit in 2012

Abstract

The neuropeptides orexins and their G protein-coupled receptors, OX(1) and OX(2), were discovered in 1998, and since then, their role has been investigated in many functions mediated by the central nervous system, including sleep and wakefulness, appetite/metabolism, stress response, reward/addiction, and analgesia. Orexins also have peripheral actions of less clear physiological significance still. Cellular responses to the orexin receptor activity are highly diverse. The receptors couple to at least three families of heterotrimeric G proteins and other proteins that ultimately regulate entities such as phospholipases and kinases, which impact on neuronal excitation, synaptic plasticity, and cell death. This article is a 10-year update of my previous review on the physiology of the orexinergic/hypocretinergic system. I seek to provide a comprehensive update of orexin physiology that spans from the molecular players in orexin receptor signaling to the systemic responses yet emphasizing the cellular physiological aspects of this system.

Autocrine Endocannabinoid Signaling through CB1 Receptors Potentiates OX1 Orexin Receptor Signaling

“…Neuropeptides orexin-A and -B are best known for their roles in the regulation of sleep/wakefulness and appetite, but many other prominent functions have also been described (reviewed in Aston-Jones et al, 2010;Scammell and Winrow, 2011;Kukkonen, 2013;Perez-Leighton et al, 2012). Orexins mediate their actions via rhodopsin family G-protein-coupled receptors (GPCRs) named OX 1 and OX 2 , which can be found in the central nervous system (CNS) but also in other parts of the body (reviewed in Scammell and Winrow, 2011;Kukkonen, 2013).…”

“…Orexins mediate their actions via rhodopsin family G-protein-coupled receptors (GPCRs) named OX 1 and OX 2 , which can be found in the central nervous system (CNS) but also in other parts of the body (reviewed in Scammell and Winrow, 2011;Kukkonen, 2013). Orexin receptor activation leads to signaling via multiple intracellular pathways (reviewed in Kukkonen, 2013). In neurons, activation of orexin receptors usually leads to depolarization through inhibition of K 1 channels or activation of nonspecific cation channels (reviewed in Kukkonen, 2013).…”

The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward

“…Accordingly, two-way ANOVA calculated for AUC values (days [7][8][9][10][11][12] showed an interaction between hole and genotype (F (1,32) =5.05, p<0.05) ( Figure 3C). …”

“…The hypocretin system has been reported to play an important role in the reward circuits and to participate in the reinforcing properties of psychostimulants, nicotine, opioids and alcohol (8,9). Several reports have described the existence of functional interactions between the hypocretin and the endocannabinoid systems, mainly in the regulation of appetite and analgesia (10). However, whether hypocretins 4 take part of the neurobiological substrate underlying the addictive properties of cannabinoids remains to be elucidated.…”

Orexin-A influences mRNA expression of some glutamatergic receptor subtypes inCarassius auratus(Actinopterygii: Cyprinidae)

“…In mammals, glutamatergic fibers make contact with orexin/hypocretin (ORX)-containing neurons in the lateral hypothalamus (Henny & Jones 2006) where these neurons regulate many physiological functions such as the sleep/wake cycle, feeding, and learning and reward processes (Kukkonen 2012). In this context, a recent study suggested a major role of iGluRs and ORX interactions since it has been shown that glutamate agonists initiate excitatory postsynaptic currents by increasing the number of c-Fos-positive hypothalamic ORX neurons (Eyigor et al 2012) as well as ORX-A-dependent anxiety-like behaviors in the bed nucleus of the stria terminalis (Lungwitz et al 2012).…”