This study utilized inhibitors of the enzymatic degradation of enkephalins to investigate the possibility that this class of opioid peptides contributes to the stress-induced antinociception seen in inflamed peripheral tissues of rats with Freund's complete adjuvant-initiated unilateral hind paw inflammation. Following a 1-min cold water swim stress, rats previously injected in both hind paws with vehicle showed a transient elevation of paw pressure threshold, which was much greater in inflamed than in noninflamed paws and returned to control levels within 15 min. This preferential antinociception was significantly pronounced and prolonged in rats previously injected bilaterally with a cocktail of the enkephalinase inhibitors thiorphan (0.2 mg intraplantar) and bestatin (0.2 mg intraplantar). The enhancement of stress-induced antinociception by thiorphan/bestatin was dose-dependently antagonized by tertiary naloxone (0.125-2 mg kg-1 s.c.). Evidence for a peripheral site of action of enkephalin-like peptides in this model was provided by the antagonism of the actions of thiorphan/bestatin by quaternary naltrexone (10-20 mg kg-1 s.c.). Systemic administration of the orally active enkephalinase inhibitor SCH 34826 (5-40 mg kg-1 i.p.) was also able to dose-dependently potentiate the preferential stress-induced antinociception in a naloxone (1 mg kg-1 s.c.) reversible manner.