In adult animals and human subjects, endogenous opioids modulate ventilation under conditions of increased airway resistance. Manifestations of this modulation include depression of tidal volume and CO2 chemosensitivity during acute flow-resistive loading in goats, and loss of flow-resistive load compensation in some patients with chronic airflow obstruction. We have suggested that opioid elaboration in this setting relieves dyspnea and possibly postpones fatigue of the respiratory muscles. In the proposed studies, the mechanisms by which opiates and opioids modulate breathing during conditions of increased airway resistance will be further explored. The first specific hypothesis is that selective inhibition of one aspect of load compensation (recruitment of expiratory muscles) is induced both by opiate drugs and by activation of the endogenous opioid system. Experiments examining the effect of morphine on separate aspects of load compensation in normal subjects will be performed. In separate experiments, the effects of naloxone on non-load compensating COPD patients will be examined to determine which aspect(s) of load compensation is lost in these patients and which is restored by naloxone. Aspects of load compensation that will be systematically analyzed are (1) increase in activity of the inspiratory muscles; (2) recruitment of expiratory muscles; and (3) prolongation of inspiratory duration. Several inspiratory and expiratory muscles will be simultaneously monitored. We will investigate the effects of both acute and sustained flow-resistive loading on electrical activity of the different respiratory muscles and will simultaneously measure length of the diaphragm in vivo by sonomicrometry. The second specific hypothesis is that footshock and dyspneic stress activate the endogenous opioid system in a similar manner and will cause a similar distribution of beta-endorphins in the brain. Each stimuli will be given to individual animals and changes in concentrations of beta-endorphins will be examined in brain structures known to contain the opioid. The proposed studies should shed more light on the interaction between opiods and breathing. They also carry clinical implications for the control of breathing in patients with chronic obstruction to airflow and for preventing hypoventilation in the face of increasing airway obstruction.
