Intake of Methadone for prolonged periods is currently widely used for the therapy of heroin addiction. Despite the well known potent respiratory effects of narcotic drugs, little is known offthe acute respiratory effects of methadone and even less is known about the chronic effects of the drug. This proposal seeks to study the effects of methadone on the chemical and neuromechanical control of breathing. The studies are designed to determine the acute effects of the drug in normal volunteers, both acute and cumulative effects in subjects on methadone maintenance, and the time-course of development of tolerance should any evidence of this phenomenon be uncovered. The aspects of the control of breathing to be studied include: the strength of the lung inflation reflex, perceptual aspects of breathing (load detection and estimation of lung volumes), responses to treadmill exercise, responses to continuous inspiratory flow-resistive loading and its interaction with hypoxia and hypercapnia, and control of breathing during sleep. These studies are not only of intrinsic interest but, as a result of some unique physiologic characteristics of patients taking methadone for prolonged periods, the experimental design will allow inferences to be made with regard to the role(s) of the CO2-sensitive chemoreflex, hypoxia-sensitive chemoreflex, and peripheral neural functions in the ventilatory response to exercise and in the generation of respiratory abnormalities during sleep.