Neurophysiological studies have shown that serotonergic ligands that bind to 5-HT1A,5-HT7 and 5-HT4 serotonin receptors in the brainstem 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-OH-DPAT, an agonist of 5-HT1A and 5-HT7 receptors, and zacopride, an agonist of 5-HT4 receptors, to establish if 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 the goats respiratory rates (P = 0.013), percentage hemoglobin oxygen saturations (P < 0.0001) and PaO₂ (F_(10,70) = 5.67 P < 0.05) and increased PaCO₂ (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, co-administered with etorphine, both attenuated the effects of etorphine; respiration rates did not decrease and the percentage hemoglobin oxygen saturations and PaO₂ 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.