Dual orexin receptor blocker suvorexant attenuates hypercapnic ventilatory augmentation in mice
Dual orexin receptor blocker suvorexant attenuates hypercapnic ventilatory augmentation in mice
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DOI：
10.1016/j.brainres.2022.148061
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发表时间：
2022-09-15
期刊：
影响因子：
2.9
通讯作者：
Okada, Yasumasa
中科院分区：
文献类型：
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作者：
Fukushi, Isato;Yokota, Shigefumi;Okada, Yasumasa
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，可抑制大脑中的唤醒系统。然而，该药物的治疗效果尚未得到充分研究。本研究旨在探讨呼吸神经元食欲素受体的表达及苏沃雷生对通气的影响。用荧光金（FG）标记法观察了4只成年小鼠（n = 4）头侧腹侧呼吸组（rVRG）向膈核（PhN）投射的神经元，（2）面旁呼吸组/小斜方后核（postertrapezoidnucleus）内配对同源框2b（Phox 2b）免疫反应阳性神经元（3）前Bo中心点tzinger复合体（preBo中心点tC）神经激肽1受体（NK 1 R）和生长抑素（SST）免疫反应阳性神经元。此外，我们在体内测量了无限制小鼠（n = 10）在苏沃雷生预处理（10和累积100 mg/kg）之前和之后对高氧高碳酸血症（5%CO2）和缺氧（10%O2）的体内缓解反应。在pFRG/RTN Phox 2b和preBo中心dot C NK 1 R/SST免疫反应阳性神经元中发现OX 2 R免疫反应阳性物质，而在FG标记的rVRG神经元中未发现OX 2 R免疫反应阳性物质，提示orexin参与呼吸控制。此外，苏沃雷生明显抑制高碳酸血症的呼吸增强，否则不影响通气。中枢食欲素参与形成高碳酸血症的缓解性化学敏感性。食欲素受体拮抗剂suvorexant对高碳酸血症缓解增强的抑制作用要求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中谨慎使用。需要临床试验来探索食欲素的靶向药理学抑制在消化性病理学中的作用。
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 neuro-kinin 1 receptor (NK1R) and somatostatin (SST) in the preBo center dot tzinger complex (preBo center dot tC). Additionally, we measured in vivo ventilatory responses to hyperoxic hypercapnia (5% CO2) and hypoxia (10% O2) 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 preBo center dot tC 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 chemo-sensitivity. 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.