In conscious, microfilaria-free, adult mongrel dogs, i.v. bolus administration of methionine enkephalin (Met5-ENK) produced a transient elevation of both inspiratory minute ventilation (VI) and heart rate (HR). Both VI and HR increased progressively with increasing doses of Met5-ENK over the range of 6 to 18 micrograms/kg, thereafter plateauing at doses up to 36 micrograms/kg. Maximum changes in VI and HR occurred within 30 to 45 sec after injection, both variables returning to control levels in approximately 2 min. In four out of five dogs, mean inspiratory flow (tidal volume/inspiratory time), and consequently, tidal volume, accounted for this enkephalin-mediated increase in ventilation. In one of the dogs, respiratory rate, rather than tidal volume, increased after Met5-ENK. This change in respiratory rate was due to an increase in "effective timing" of the respiratory cycle, the latter defined as the ratio of inspiratory time to total respiratory time. Despite significant changes in VI and HR, neither end tidal oxygen nor carbon dioxide levels were significantly different from control after i.v. injections of Met5-ENK. Pretreatment with naltrexone methylbromide, a quaternary opiate antagonist that does not cross the blood-brain barrier, abolished all enkephalin-induced changes in VI and HR, thus suggesting that systemic enkephalins modulate ventilation via opiate receptors outside the blood-brain barrier. Activation of these receptors produce an increase in both cardiovascular and respiratory activity, as one might expect during stress conditions. These data further support a potential role for peripheral enkephalins as excitatory stress hormones.