Wu Jian, Li Peng, Wu Xiuying
Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, 110004, China.
Department of Respiratory Medicine, Shengjing Hospital, China Medical University, Shenyang, China.
Sleep Breath. 2017 Mar;21(1):227-233. doi: 10.1007/s11325-016-1448-3. Epub 2017 Jan 3.
Chronic intermittent hypoxia (CIH) is a characteristic of obstructive sleep apnea syndromes (OSAs). Recurrent hypoxia during the developmental period increases respiratory sensitivity to subsequent administration of opioids. However, it is unknown whether CIH affects respiratory sensitivity to opioids in adults. Our study aimed to assess the changes in respiratory sensitivity to morphine (MOR) under CIH and to explore the possible mechanisms in an adult rat model.
We applied CIH in adult Sprague-Dawley rats to simulate the hypoxia condition caused by OSAs. An atmosphere with room air was applied as the control environment. After 4 weeks of CIH, MOR was administered. Tests of respiratory function, including measurement of tidal volume (Vt), minute ventilation (MV), tidal volume divided by inspiratory time (Vt/Ti), and respiratory frequency (RF), were then performed. HIF-1α, δ-OR, and μ-OR expressions in the medulla were measured.
After MOR administration, Vt, MV, RF, and Vt/Ti decreased in both the CIH and control groups. MOR caused a more profound depression of MV, RF, Vt, and Vt/Ti in CIH + MOR group compared with C + MOR group. Administration of either μ-OR-specific antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, or δ-OR-specific antagonist, naltrindole, attenuated the depression of Vt, MV, RF, and Vt/Ti. Intermittent hypoxia markedly increased the expression of δ-OR and μ-OR in the medullas of rats. HIF-1α protein expression increased significantly, and HIF-1α mRNA levels remained unchanged.
CIH increases the respiratory sensitivity of rats to MOR by upregulating expression of μ-OR and δ-OR in the medulla, which might be associated with increased levels of HIF-1α.
慢性间歇性缺氧（CIH）是阻塞性睡眠呼吸暂停综合征（OSA）的一个特征。发育期反复缺氧会增加对随后给予阿片类药物的呼吸敏感性。然而，CIH是否会影响成年人对阿片类药物的呼吸敏感性尚不清楚。我们的研究旨在评估成年大鼠模型中CIH条件下对吗啡（MOR）呼吸敏感性的变化，并探讨其可能机制。
我们对成年Sprague-Dawley大鼠施加CIH以模拟OSA引起的缺氧状况。以室内空气作为对照环境。CIH处理4周后，给予MOR。然后进行呼吸功能测试，包括潮气量（Vt）、分钟通气量（MV）、潮气量除以吸气时间（Vt/Ti）和呼吸频率（RF）的测量。测量延髓中HIF-1α、δ-阿片受体（δ-OR）和μ-阿片受体（μ-OR）的表达。
给予MOR后，CIH组和对照组的Vt、MV、RF和Vt/Ti均降低。与C + MOR组相比，MOR导致CIH + MOR组的MV、RF、Vt和Vt/Ti下降更显著。给予μ-OR特异性拮抗剂D-苯丙氨酸-半胱氨酸-酪氨酸-D-色氨酸-鸟氨酸-苏氨酸-苯丙氨酸-苏氨酸-酰胺（D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2）或δ-OR特异性拮抗剂纳曲吲哚可减轻Vt、MV、RF和Vt/Ti的下降。间歇性缺氧显著增加大鼠延髓中δ-OR和μ-OR的表达。HIF-1α蛋白表达显著增加，而HIF-1α mRNA水平保持不变。
CIH通过上调延髓中μ-OR和δ-OR的表达增加大鼠对MOR的呼吸敏感性，这可能与HIF-1α水平升高有关。
