Innovations In Clinical Neuroscience

MAR-APR 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 3 – 4 , M A R C H – A P R I L 2 0 1 7 ] 35 It was demonstrated that i.c.v. injection of orexin increased blood pressure, heart rate, and renal sympathetic nerve activity. These effects were abolished by administration of α- or β-adrenoceptor antagonists. In addition, a high dose of orexin increased plasma noradrenaline (NA) concentration, 38 which suggests that orexin increases sympathetic nerve tone. The autonomic response induced by orexin A is greater than that induced by orexin B. The novel OX1R antagonist SB-334867, which alone did not significantly change baseline hemodynamic variables and plasma catecholamine levels, markedly attenuated increase in mean arterial pressure, heart rate, and plasma noradrenaline concentration induced by orexin-A in rats. 12 Li A et al 39 measured orexin-A mRNA expression in the rostral ventrolateral medulla and anatomized both orexin receptors using an orally administered potent dual orexin receptor antagonist, almorexant, in spontaneously hypertensive rats. The researchers found there was a strong trend toward an increased orexin-A mRNA expression in the rostral ventrolateral medulla, and blocking orexin receptors markedly lowered blood pressure, heart rate, sympathetic vasomotor tone, and the noradrenaline levels in cerebrospinal fluid and plasma. These results suggest that orexin A positively regulates sympathetic nerve tone primarily through the OX 1 R. Therefore, suvorexant might attenuate some of the sympathetic nervous system markers. There is much evidence showing that orexin might play a role in the regulation of the HPA axis via a central mechanism. 14,15 I.c.v injection of both orexin A and orexin B was shown to activate neurons in the paraventricular nucleus (PVN) and to increase plasma adrenocorticotrophin (ACTH) and corticosteroid levels in rats. 14,40 As orexin neurons innervate the PVN in which OX 2 R is abundantly expressed, 41,42 this response might be mediated by corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) in the PVN. The effect of centrally injected orexins on HPA axis function was completely inhibited by a CRH receptor antagonist, demonstrating the ability of orexins to activate hypothalamic CRH neurons in the PVN, most likely via the OX 2 R, with subsequent activation of the HPA axis. However, other studies suggest that orexin might activate adrenocortical cells without involvement of the HPA axis. In one study, chronic administration of orexin for one week did not affect plasma ACTH levels, but increased plasma cortisol and aldosterone levels. 43 In another study, orexin increased cortisol secretion in a dose-dependent manner using freshly dispersed normal and adenomatous human adrenocortical cells. 44 In fact, it was reported that orexin-deficient, male patients with narcolepsy displayed blunted basal and total ACTH production without basal pulsatile cortisol secretion. 45 These studies suggest that orexin might directly activate adrenocortical cells in the adrenal gland where OX 1 R, OX 2 R are distributed, without an involvement of the HPA axis responsiveness to different type of stress via CRH and AVP neurons in the PVN. Whether these observations have any practical implications in narcolepsy or other sleep disorders remains to be studied. The reduction of white blood cell count after suvorexant treatment may be linked with the significant decrease of cortisol levels and slight decrease of noradrenaline levels, because glucocorticoid and catecholamine are known to induce leukocytosis by several biological mechanism. 46,47 Patel et al 48 reported that the low- dose pharmacology of dual orexin receptor antagonist, SB-649868, had no impact on neuroendocrine hormones (cortisol, ACTH, and prolactin) and most sympathetic nervous system markers (pulse rate, mean arterial blood pressure, plasma noradrenaline, and adrenaline) in insulin-induced hypoglycemic stress in 24 healthy male subjects. The investigators also indicated the exploring the utility of the insulin tolerance test model as a basis for evaluating orexinergic antagonism over a wider dose range, including doses known to have efficiency on other marker, such as measures of insomnia. Limitations. There are several limitations to the present study. First, subjects were selected under rigorous criteria to investigate the effect of suvorexant treatment; nevertheless, most of them received some psychiatric and/or medical treatment. In particular, the use psychotropic medications is a confounder in this study. Second, it was an open-label study, not a double-blind study design, with a small sample size and a limited observation period. Third, we assumed that the closed-ward setting would minimize inter-individual differences in sleep habituation, energy intake, and expenditure; however, some patients were discharged before the study ended, and it would have been difficult to evaluate these subjects as outpatients. Fourth, serum markers were measured and compared at only one point in the day, so that circadian variation patterns of neuroendocrine hormones were not taken into account. CONCLUSION The results of the present study could be summarized as follows: In psychiatric inpatients being treated with suvorexant for sleep disorders, 1) suvorexant was effective in improving the quality of sleep in general, especially subjective sleep quality, sleep duration, and habitual sleep efficiency; 2) suvorexant ameliorated the severity of anxiety and depression; 3) suvorexant slightly attenuated the sympathetic nervous system markers (fasting plasma noradrenaline level and pulse rate) and had no certain effect on fasting plasma prolactin and insulin; and 4) suvorexant reduced the hypothalamus-pituitary-adrenal axis markers (fasting plasma cortisol level and white blood cell count). Further studies investigating the role that suvorexant plays in the coordination of central and peripheral states of the CNS need to be performed in various "real- world" treatment settings to further support our conclusion. ACKNOWLEDGMENT The authors would like to thank our colleagues in all department of Kusatsu Hospital for their assistance with this report.

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