The goal of this research program is to define central and peripheral mechanisms that determine or influence the generation of breathing movements of the fetus in utero and at birth. Toward this end we developed and validated the fetal CO2 response test, which permits quantification of threshold and responsiveness to CO2 as reliable indexes of respiratory center activity in the fetus. These studies revealed that the CO2 threshold of the fetus is significantly higher than that of the adults; nonspecific somatic stimulation lowers this threshold; and endogenous (natural) opioids may also be factors in the physiologic suppression of breathing in fetal life. In other studies we found that theophylline is a respiratory center stimulant for the fetus over a wide range of fetal PaO2 and pH in so far as it lowers CO2 threshold and elevates respiratory center activity significantly and that arousal is a requisite for generation and maintenance of fetal breathing. We have also shown that fetal respiratory control is modulated by temperature, particularly core body temperature and that the onset of breathing in the fetus in which the trachea is occluded has the characteristics of the "progressive response to airway occlusion" which has been described in adults. Whereas the latter has been attributed to concurrent changes in blood gases, this is not the case for the fetus in which PaO2 and PaCO2 are unchanged during occlusion. We have also found that beta-endorphin, when administered directly into cerebrospinal fluid of adult dogs, depresses both frequency and tidal volume of respiration and that the effect on frequency is progressive and longer lasting. (It also produces hypotension and bradycardia, as others have shown). Interestingly, the frequency effect was negligible following vagotomy and Naloxone (a specific opioid antagonist) reversed both the cardiovascular and pulmonary effects of beta-endorphin. In summary, our studies have shown that fetal respiratory center activity may be monitored reliably and quantitatively in utero. They have given added insight into possible mechanisms of natural suppression (high CO2 threshold and endogenous opioids) and facilitation (somatic and visceral afferents, chemical stimuli) of fetal breathing and also of the action of drugs (theophylline) that may be useful clinically to alter respiratory center activity.