Faculty of Health Sciences, Aomori University of Health and Welfare, Aomori, Japan; Clinical Research Center, Murayama Medical Center, Musashimurayama, Japan.
Department of Anatomy and Neuroscience, Shimane University School of Medicine, Izumo, Japan.
Brain Res. 2022 Nov 15;1795:148061. doi: 10.1016/j.brainres.2022.148061. Epub 2022 Aug 28.
Suvorexant (Belsomra(R)), a dual orexin receptor antagonist widely used in the treatment of insomnia, inhibits the arousal system in the brain. However, the drug's ventilatory effects have not been fully explored. This study aims to investigate the expression of orexin receptors in respiratory neurons and the effects of suvorexant on ventilation. Immunohistology of brainstem orexin receptor OX2R expression was performed in adult mice (n = 4) in (1) rostral ventral respiratory group (rVRG) neurons projecting to the phrenic nucleus (PhN) retrogradely labeled by Fluoro-Gold (FG) tracer, (2) neurons immunoreactive for paired like homeobox 2b (Phox2b) in the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), and (3) neurons immunoreactive for neurokinin 1 receptor (NK1R) and somatostatin (SST) in the preBötzinger complex (preBötC). Additionally, we measured in vivo ventilatory responses to hyperoxic hypercapnia (5% CO) and hypoxia (10% O) before and after suvorexant pretreatment (10 and cumulative 100 mg/kg) in unrestrained mice (n = 10) in a body plethysmograph. We found the OX2R immunoreactive materials in pFRG/RTN Phox2b and preBötC NK1R/SST immunoreactive neurons but not in FG-labeled rVRG neurons, which suggests the involvement of orexin in respiratory control. Further, suvorexant expressly suppressed the hypercapnic ventilatory augmentation, otherwise unaffecting ventilation. Central orexin is involved in shaping the hypercapnic ventilatory chemosensitivity. Suppression of hypercapnic ventilatory augmentation by the orexin receptor antagonist suvorexant calls for caution in its use in pathologies that may progress to hypercapnic respiratory failure, or sleep-disordered breathing. Clinical trials are required to explore the role of targeted pharmacological inhibition of orexin in ventilatory pathologies.
苏沃雷生（Belsomra(R)）是一种广泛用于治疗失眠的双重食欲素受体拮抗剂，它抑制大脑的觉醒系统。然而，该药物的通气作用尚未得到充分探索。本研究旨在探讨食欲素受体在呼吸神经元中的表达以及苏沃雷生对通气的影响。在成年小鼠（n=4）中，通过荧光金（FG）示踪剂逆行标记的呼吸前腹侧群（rVRG）神经元、副神经核/梯形核（pFRG/RTN）中成对样同源框 2b（Phox2b）免疫反应性神经元以及 PreBötzinger 复合体（preBötC）中神经激肽 1 受体（NK1R）和生长抑素（SST）免疫反应性神经元中进行脑干部位食欲素受体 OX2R 表达的免疫组织化学研究。此外，我们在未束缚的小鼠（n=10）的体描箱中测量了苏沃雷生预处理（10 和累积 100mg/kg）前后对高氧高碳酸血症（5%CO）和缺氧（10%O）的体内通气反应。我们发现 OX2R 免疫反应物质存在于 pFRG/RTN Phox2b 和 preBötC NK1R/SST 免疫反应性神经元中，但不存在于 FG 标记的 rVRG 神经元中，这表明食欲素参与了呼吸控制。此外，苏沃雷生明确抑制了高碳酸血症通气增强，而对通气没有其他影响。中枢食欲素参与调节高碳酸血症通气化学敏感性。食欲素受体拮抗剂苏沃雷生抑制高碳酸血症通气增强，在可能进展为高碳酸血症呼吸衰竭或睡眠呼吸障碍的病理情况下使用时需要谨慎。需要进行临床试验来探索靶向抑制食欲素在通气病理中的作用。
