Orexin B (rat, mouse)

In this review, we focus on the role of orexin signaling in blood pressure control and its potential link to hypertension by summarizing evidence from several experimental animal models of hypertension. Studies using the spontaneously hypertensive rat (SHR) animal model of human essential hypertension show that pharmacological blockade of orexin receptors reduces blood pressure in SHRs but not in Wistar-Kyoto rats. In addition, increased activity of the orexin system contributes to elevated blood pressure and sympathetic nerve activity (SNA) in dark-active period Schlager hypertensive (BPH/2J) mice, another genetic model of neurogenic hypertension. Similar to these two models, Sprague-Dawley rats with stress-induced hypertension display an overactive central orexin system. Furthermore, upregulation of the orexin receptor 1 increases firing of hypothalamic paraventricular nucleus neurons, augments SNA, and contributes to hypertension in the obese Zucker rat, an animal model of obesity-related hypertension. Finally, we propose a hypothesis for the implication of the orexin system in salt-sensitive hypertension. All of this evidence, coupled with the important role of elevated SNA in increasing blood pressure, strongly suggests that hyperactivity of the orexin system contributes to hypertension.

Orexins/hypocretins are recently discovered neuropeptides synthetized mainly by neurons located in the posterolateral hypothalamus. Hypocretin-1 and -2 are the same peptides as orexin-A and orexin-B. Orexin A is a 33 amino acid peptide with N-terminal pyroglutamyl residue and two intrachain disulphide bonds. Orexin B is a linear peptide of 28 amino acids. These two peptides are potent agonists at both the orexin-1 (OxR1) and orexin-2 (OxR2) receptors. Orexin-A is selective ligand for OxR1 and OX2 binds both orexins. The structure of orexins and their receptors is highly conservative in mammals. Orexin A sequence is identical in several mammalian species (human, mouse, rat, bovine and porcine). Intracerebroventricular administered orexin-A stimulates food intake and energy expenditure. Orexins are also involved in the regulation of neurohormones and pituitary hormones secretion as well as in the control of cardiovascular and sleep-wake function. Orexins also play a role in the pathogenesis of narcolepsy. Mutation in the gene coding preproorexin or OxR2 receptor gene results in narcolepsy in mice and canine. In patients with narcolepsy orexin neurotransmission was altered and orexin level in cerebrospinal fluid was undetectable.

The hypocretins/orexins were discovered in 1998. Within 2 years, this led to the discovery of the cause of human narcolepsy, a 90% loss of hypothalamic neurons containing these peptides. Further work demonstrated that these neurons were not simply linked to waking. Rather these neurons were active during pleasurable behaviors in waking and were silenced by aversive stimulation. This was seen in wild-type mice, rats, cats, and dogs. It was also evident in humans, with increased Hcrt release during pleasurable activities and decreased release, to the levels seen in sleep, during pain. We found that human heroin addicts have, on average, an increase of 54% in the number of detectable Hcrt neurons compared to "control" human brains and that these Hcrt neurons are substantially smaller than those in control brains. We found that in mice, chronic morphine administration induced the same changes in Hcrt neuron number and size. Our studies in the mouse allowed us to determine the specificity, dose response relations, time course of the change in the number of Hcrt neurons, and that the increased number of Hcrt neurons after opiates was not due to neurogenesis. Furthermore, we found that it took a month or longer for these anatomical changes in the mouse brain to return to baseline. Human narcoleptics, despite their prescribed use of several commonly addictive drugs, do not show significant evidence of dose escalation or substance use disorder. Similarly, mice in which the peptide has been eliminated are resistant to addiction. These findings are consistent with the concept that an increased number of Hcrt neurons may underlie and maintain opioid or cocaine use disorders.