Sighs, a well known phenomenon in mammals, are substantially augmented by hypoxia and hypercapnia. Because systemic and local DAMGO, a µ-receptor agonist, in the caudal medullary raphe region (cMRR) decreased the ventilatory response to hypoxia and hypercapnia, we hypothesized that these treatments could inhibit sigh responses to these chemical stimuli. The number and amplitude of sighs were recorded during three levels of isocapnic hypoxia (15%, 10% and 5% O₂ for 1.5 min) or hypercapnia (3%, 7% and 10% CO₂ for 4 min) to test the dependency of sigh responses on the intensity of chemical drive in anesthetized and spontaneously breathing rats. The role of µ-receptors in modulating sigh responses to 10% O₂ or 7% CO₂ were subsequently evaluated by comparing the sighs before and after: (1) intravenous administration of DAMGO (100 ug/kg); (2) microinjection of DAMGO (35 ng/100 nl) into the cMRR; and (3) intravenous administration of DAMGO following CTAP microinjection (100 ng/100 nl), a µ-receptor antagonist, into the cMRR. Hypoxia and hypercapnia increased the number of sighs, but not amplitude, in a concentration-dependent manner, and the responses to hypoxia were significantly greater than those to hypercapnia. Systemic and local injection of DAMGO into the cMRR predominantly decreased the number of sighs, while microinjection into the rostral and middle MRR had no or limited effects. Microinjecting CTAP into the cMRR significantly diminished the systemic DAMGO-induced reduction of the number of sighs in response to hypoxia, but not to hypercapnia. Hypoxia and hypercapnia elevate the number of sighs in a concentration-dependent manner in anesthetized rats, and this response is significantly depressed by activating systemic µ-receptors, especially those within the cMRR.