Meyer Leith C R, Fuller Andrea, Mitchell Duncan
Brain Function Research Unit, School of Physiology, University of the Witwatersrand, South Africa.
Am J Physiol Regul Integr Comp Physiol. 2006 Feb;290(2):R405-13. doi: 10.1152/ajpregu.00440.2005. Epub 2005 Sep 15.
Neurophysiological studies have shown that serotonergic ligands that bind to 5-HT1A, 5-HT7, and 5-HT4 serotonin receptors in brain stem have beneficial effects on respiratory neurons during opioid-induced respiratory depression. The effect of these ligands on respiratory function and pulmonary performance has not been studied. We therefore examined the effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an agonist of 5-HT1A and 5-HT7 receptors, and zacopride, an agonist of 5-HT4 receptors, to establish whether these ligands would reverse opioid-induced respiratory depression and hypoxia without affecting the immobilizing properties of the opioid drug etorphine. When etorphine was used to sedate and immobilize goats, it significantly decreased respiratory rate (P = 0.013), percent hemoglobin oxygen saturation (P < 0.0001), and arterial oxygen partial pressure [Pa(O2); F(10,70) = 5.67, P < 0.05] and increased arterial carbon dioxide partial pressure [F(10,70) = 3.87, P < 0.05] and alveolar-arterial oxygen partial pressure gradient [A-a gradients; F(10,70) = 8.23, P < 0.0001]. Zacopride and 8-OH-DPAT, coadministered with etorphine, both attenuated the effects of etorphine; respiration rates did not decrease, and percent hemoglobin oxygen saturation and Pa(O2) remained elevated. Zacopride decreased the hypercapnia, indicating an improvement in ventilation, whereas 8-OH-DPAT did not affect the hypercapnia and, therefore, did not improve ventilation. The main beneficial effect of 8-OH-DPAT was on the pulmonary circulation; it improved oxygen diffusion, indicated by the normal A-a gradients, presumably by improving ventilation perfusion ratios. Neither zacopride nor 8-OH-DPAT reversed etorphine-induced catatonic immobilization. We conclude that serotonergic drugs that act on 5-HT1A, 5-HT7, and 5-HT4 receptors reverse opioid-induced respiratory depression and hypoxia without reversing catatonic immobilization.
神经生理学研究表明，与脑干中的5-HT1A、5-HT7和5-HT4血清素受体结合的血清素能配体在阿片类药物引起的呼吸抑制期间对呼吸神经元具有有益作用。这些配体对呼吸功能和肺性能的影响尚未得到研究。因此，我们研究了5-HT1A和5-HT7受体激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）以及5-HT4受体激动剂扎考必利的作用，以确定这些配体是否能逆转阿片类药物引起的呼吸抑制和缺氧，同时又不影响阿片类药物埃托啡的麻醉作用。当使用埃托啡对山羊进行镇静和麻醉时，它显著降低了呼吸频率（P = 0.013）、血红蛋白氧饱和度百分比（P < 0.0001）和动脉血氧分压[Pa(O2); F(10,70) = 5.67, P < 0.05]，并增加了动脉血二氧化碳分压[F(10,70) = 3.87, P < 0.05]和肺泡-动脉血氧分压差[A-a梯度; F(10,70) = 8.23, P < 0.0001]。与埃托啡联合使用时，扎考必利和8-OH-DPAT均减弱了埃托啡的作用；呼吸频率没有降低，血红蛋白氧饱和度百分比和Pa(O2)仍保持升高。扎考必利降低了高碳酸血症，表明通气有所改善，而8-OH-DPAT没有影响高碳酸血症，因此没有改善通气。8-OH-DPAT的主要有益作用在于肺循环；它改善了氧扩散，这由正常的A-a梯度表明，可能是通过改善通气灌注比实现的。扎考必利和8-OH-DPAT均未逆转埃托啡引起的紧张性麻痹。我们得出结论，作用于5-HT1A、5-HT7和5-HT4受体的血清素能药物可逆转阿片类药物引起的呼吸抑制和缺氧，而不会逆转紧张性麻痹。
