Neuropeptides ‘hypocretins

Hypocretin A wakefulness-promoting hypothalamic neuropeptide, a deficiency of which is involved in the pathophysiology of narcolepsy. 

Other activators of the histaminergic system may also be involved in wakefulness. The orexin (i.e. hypocretin) A and B neuropeptides were isolated from rat hypothalamic extracts. A mutation in the orexin-2 receptor gene was found to be associated with canine narcolepsy, and mice lacking the orexin peptide display increases in REM and NREM sleep and a decrease in wakefulness time during the active period of normal rodents. However, the exact role of orexin in physiological sleep and the mechanisms involved have not yet been elucidated. 

Fu L. Y., Acuna-Goycolea C., van den Pol A. N. (2004). Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms tonic depression of the hypothalamic arousal system. J. Neurosci. 

Control of feeding behavior involves peripheral peptides (insulin, ghrelin, leptin) plus several peptides in the CNS (orexins/hypocretins, CCK, galanin, MSH, neuropeptide Y, CRH, cocaine-and-amphetamine-regulated transcript (CART)) [35, 36]. Some of the same peptides are involved in reward systems crucial to drug addiction. Specific receptor blockers are being tested for many of these peptide-receptor systems, with the hope of very selective actins with minimal side effects [35], For example, there are two CCK receptor subtypes, CCK-A and... 

Smith BN, Davis SF, van den Pol AN et al (2002) Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2. Neuroscience 115 707-14 Smith-White MA, Herzog H, Potter EK (2002) Role of neuropeptide Y Y2 receptors in modulation of cardiac parasympathetic neurotransmission. Regul Peptides 103 105-11 Stanford IM, Cooper Al (1999) Presynaptic mu and delta opioid receptor modulation of GABAa IPSCs in the rat globus pallidus in vitro. 1 Neurosci 19 4796 4803 Starke K (1977) Regulation of noradrenaline release by presynaptic receptor systems. Rev Physiol Biochem Pharmacol 77 1-124... 

Tu B, Timofeeva O, Jiao Y et al (2005) Spontaneous release of neuropeptide Y tonically inhibits recurrent mossy fiber synaptic transmission in epileptic brain. J Neurosci 25 1718-29 Ueda H, Fukushima N, Ge M et al (1987) Presynaptic opioid kappa-receptor and regulation of the release of Met-enkephalin in the rat brainstem. Neurosci Lett 81 309-13 van den Pol AN, Gao XB, Obrietan K et al (1998) Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci 18 7962-71... 

GPCR variant relevance to disease and drug response phenotypes may be useful in modeling systems suitable for drug development— such as targeting such systems as the orexin/hypocretin neuropeptides [37]. Such analyses are, however, complicated by the variability across different populations. 

Broberger C, DeLeceaL, Sutcliffe JG, HokfeltT. Hypocretin/orexin- and melanin-concentrating hormoneexpressing cells form distinct populations in the rodent lateral hypothalamus relationship to the neuropeptide Y and agouti gene-related protein systems. J Compar Neurol 1998 402 460-474. 

The whole field of research can reasonably be described as being revolutionized over a few years at the turn of the century through the discovery of two neuropeptide transmitters produced by cells of the hypothalamus. These hypocretins (Hcrt-1 and Hcrt-2), which are also known as orexins, are clearly the key to understanding narcolepsy, and a good deal of the normal sleep mechanism. The familial canine narcolepsy cases are associated with genetic mutations of this system, mice with targeted deletions of the gene for the precursor of these peptides display symptoms of narcolepsy, and the majority of humans with narcolepsy and the associated HLA characteristics have no detectable hypocretins in their cerebrospinal fluid. 

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