The effect of chronic intermittent hypoxia on respiratory sensitivity to morphine in rats.

PURPOSE: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.