HP 228 is a synthetic heptapeptide analog of alpha-MSH that attenuates the production and release of inflammatory cytokines. The purpose of this study was to define HP 228's effects, alone and in combination with morphine, on resting ventilation and the ventilatory response to hypoxia and hypercarbia. Six healthy nonsmoking young adult males completed the four-session experiment. Subjects first underwent an initial training session. During subsequent sessions, each subject was tested for the respiratory effects of intravenous HP 228 (30 microg/kg), morphine (0.15 mg/kg), or HP 228 (30 microg/kg) plus morphine (0.15 mg/kg) in a double-blind placebo-controlled randomized balanced within-subjects experimental design. Sessions began with baseline measurement of resting ventilation, oxygen consumption, the isocapnic hypoxic ventilatory response (HVR), and normoxic hypercapnic ventilatory response (HCVR). A second set of respiratory measurements were obtained 10 min after completion of HP 228 or placebo infusion. Morphine or placebo was then administered and ventilatory responses were determined 15 and 40 min postinfusion. HP 228 produced cutaneous flushing, but had no significant effect on respiration or hemodynamics. Morphine significantly decreased metabolism, resting ventilation, and hypoxic and hypercarbic ventilatory responsiveness, independent of prior HP 228 administration. A seventh subject experienced a significant cardiac arrhythmia upon exposure to hypoxia after receiving both HP 228 and morphine and was withdrawn from further study. In conclusion, in this early Phase I clinical trial, HP 228 was found to neither depress ventilation nor augment morphine-induced respiratory depression in healthy young males.