Over the last several years, it has been recognized that the body generates substances with opioid activity under specific physiologic and pathologic situations. This has elicited considerable interest regarding breathing in view of the potent respiratory depressant effects of opiate drugs. The proposed studies will continue to examine the role of these endogenously generated opiates (i.e., endorphins) on respiration and gas exchange. Utilizing both direct assays of beta-endorphin activity and reversal by the opiate antagonist naloxone of the postulated endorphin effects on breathing, three general areas selected on the basis that endorphins are known to be released or effects reminiscent of morphine are manifested will be studied. In normal human volunteers, the effects of non-stress-induced (Metyrapone) endorphin elaboration on ventilation and the control of breathing during wakefulness and sleep will be evaluated. The hypothesis that these endorphins will modify and depress breathing and generate sleep-related irregularities of breathing will be tested. In patients with Chronic Obstructive Pulmonary Disease (COPD), the hypothesis that endorphin elaboration is the mechanism for the relief of dyspnea by exercise rehabilitation will be examined. Finally, in animal models of airway obstruction and lung injury, endorphin release and their effects on respiration and gas exchange will be investigated; the hypothesis that endogenously generated opiates contribute to the generation of fatigue, minimize the magnitude of the shunt-like hypoxia of acute lung injury and help generate the ventilatory adaptations (i.e., impaired load compensation) to chronic airway obstruction should be elucidated. The proposed studies directly bear on the understanding of several clinical problems including emphysema, sleep apnea and the Adult Respiratory Distress Syndrome. Identifying endorphin influences in these conditions should improve our ability to predict the ventilatory responses of these patients.
