This study examined antinociception induced through the activation of local opioid receptors in inflammation by endogenous opioids. Rats developed a unilateral localized inflammation upon injection of Freund's adjuvant into one hindpaw. Four to 6 d later they were subjected to cold water swim (CWS), an environmental stimulus known to activate intrinsic opioid systems. Following CWS (1 min) the animals' withdrawal threshold to noxious pressure applied onto the paws increased significantly more on the inflamed paw than on the noninflamed paw. This unilateral antinociceptive effect in inflamed paws was dose-dependently and stereospecifically reversible by intraplantar (i.pl.) but not systemic (i.v. or s.c.) administration of the opioid antagonist naloxone (18 micrograms). This suggested that CWS- induced antinociception in inflamed tissue was brought about by the activation of local opioid receptors. Antiinflammatory or vasoconstrictive events, as measured by paw volume and temperature, did not contribute to this unilateral antinociception. Receptor-selective antagonists indicated the involvement of mu- and delta- but not kappa- receptors. Intravenous application of a universal antibody to endogenous opioid peptides (3-E7) and a specific antibody to beta- endorphin, but not antisera against metenkephalin or dynorphin, abolished the CWS effect. Finally, the i.pl. injection of synthetic beta-endorphin (1–31) produced an antinociceptive effect in inflamed paws which was reversible by i.pl. naloxone and selective mu- and delta- receptor antagonists. These findings suggest that antinociception in inflamed tissue can be induced through the activation of local opioid receptors by endogenous beta-endorphin released during CWS.