Hypocretin/Orexin Neuropeptides: Participation in the Control of Sleep-Wakefulness Cycle and Energy Homeostasis

Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Current Neuropharmacology (Impact Factor: 3.05). 04/2009; 7(1):50-9. DOI: 10.2174/157015909787602797
Source: PubMed

ABSTRACT Hypocretins or orexins (Hcrt/Orx) are hypothalamic neuropeptides that are synthesized by neurons located mainly in the perifornical area of the posterolateral hypothalamus. These hypothalamic neurons are the origin of an extensive and divergent projection system innervating numerous structures of the central nervous system. In recent years it has become clear that these neuropeptides are involved in the regulation of many organic functions, such as feeding, thermoregulation and neuroendocrine and cardiovascular control, as well as in the control of the sleep-wakefulness cycle. In this respect, Hcrt/Orx activate two subtypes of G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R) that show a partly segregated and prominent distribution in neural structures involved in sleep-wakefulness regulation. Wakefulness-enhancing and/or sleep-suppressing actions of Hcrt/Orx have been reported in specific areas of the brainstem. Moreover, presently there are animal models of human narcolepsy consisting in modifications of Hcrt/Orx receptors or absence of these peptides. This strongly suggests that narcolepsy is the direct consequence of a hypofunction of the Hcrt/Orx system, which is most likely due to Hcrt/Orx neurons degeneration.
The main focus of this review is to update and illustrate the available data on the actions of Hcrt/Orx neuropeptides with special interest in their participation in the control of the sleep-wakefulness cycle and the regulation of energy homeostasis. Current pharmacological treatment of narcolepsy is also discussed.

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Available from: Angel Nuñez, Sep 27, 2015
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    • "Although the total number of orexin neurons is fairly small, axonal projections from these cells extend from the LH to many regions of the rat brain and spinal cord (Chen et al. 1999; Nixon and Smale 2007; Cutler et al. 1999; Date et al. 1999; Peyron et al. 1998; Nambu et al. 1999), and the distribution of these neurons and axonal projections is very similar across rodent strains and species (Nixon and Smale 2007). The overall distribution of orexin fibers in the brain and spinal cord allows this small population of neurons to play roles in integrating multiple autonomic and behavioral functions, primarily feeding, sleep/wake behavior, and arousal (Niimi et al. 2001a; Kotz et al. 2002; Rodgers et al. 2000; Kunii et al. 1999; Haynes et al. 2000; Mondal et al. 1999; Yamanaka et al. 2000; Tsujino and Sakurai 2009; Nunez et al. 2009; Siegel 1999; Lin et al. 1999; Piper et al. 2000; Hungs and Mignot 2001), as well as nociception, respiratory, motor, neuroendocrine, and cardiovascular systems (Nixon and Smale 2007; Cutler et al. 1999; Date et al. 1999; Peyron et al. 1998; Nambu et al. 1999; Volgin et al. 2002; Zhang and Luo 2002; Samson et al. 1999; Shirasaka et al. 2002; Zhang et al. 2005a; Berthoud et al. 2005). Disruptions or deficiencies in orexin signaling have been linked to a number of sleep/wake and endocrine disorders in humans and in animal models (Lin et al. 1999; Petersén et al. 2005; Nevsimalova et al. 2005; Thannickal et al. 2000; Nishino et al. 2000). "
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    ABSTRACT: In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus-perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin-producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.
    Handbook of experimental pharmacology 01/2012; 209(209):77-109. DOI:10.1007/978-3-642-24716-3_4
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    • "The perifornical-lateral hypothalamic area (PF-LHA) has been implicated in the regulation of many physiological functions, including locomotor activity and sleep-wake control (Gerashchenko and Shiromani, 2004, Datta and Maclean, 2007, McCarley, 2007, Szymusiak and McGinty, 2008, Nunez et al., 2009). PF-LHA contains a heterogeneous population of neurons including those expressing glutamate, hypocretin (HCRT), melanin-concentrating hormone (MCH), and GABA (Bittencourt et al., 1992, Abrahamson and Moore, 2001). "
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    ABSTRACT: The perifornical-lateral hypothalamic area (PF-LHA) is a major wake-promoting structure. It predominantly contains neurons that are active during behavioral and cortical activation. PF-LHA stimulation produces arousal and PF-LHA lesions produce somnolence. Nitric oxide (NO) is a gaseous neurotransmitter that has been implicated in the regulation of multiple pathological and physiological processes including the regulation of sleep. NO levels are higher in the cortex and in the basal forebrain (BF) during arousal. In this study we determined whether NO levels increase in the PF-LHA during prolonged arousal and whether increased NO modulates the discharge activity of PF-LHA neurons. Experiments were conducted during lights-on phase between 8.00 and 20.00 h (lights-on at 8.00 h). First, we quantified levels of NO metabolites, NO2- and NO3- (collectively called NOx-) in the microdialysis dialysates collected from the PF-LHA during baseline (undisturbed rats), 6 h of sleep deprivation (SD), and recovery after SD. We further determined the effects of a NO donor, NOC-18, on the discharge activity of PF-LHA neurons in urethane-anesthetized rats. Overall, SD significantly affected NOx- production in the PF-LHA (one way repeated measures ANOVA, F=7.827, P=0.004). The levels of NOx- increased progressively in animals that were subjected to prolonged arousal as compared to the undisturbed predominantly sleeping animals and decreased during the recovery period. Local application of NOC-18 significantly suppressed the discharge of PF-LHA neurons including a majority of stimulus-on neurons or neurons exhibiting activation during electroencephalogram (EEG) desynchronization. The findings of this study suggest that in the PF-LHA, NO production is elevated during prolonged waking and that NO exerts predominantly inhibitory effects on PF-LHA neurons, especially on those neurons that are active during cortical activation. These findings are consistent with a hypothesis that NO in the PF-LHA plays a role in sleep regulation by inhibiting its neurons.
    Neuroscience 04/2011; 179:159-69. DOI:10.1016/j.neuroscience.2011.01.052 · 3.36 Impact Factor
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