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.