Endomorphins (EMs) are endogenous selective μ-opioid receptor agonists. Their role in inflammatory pain has not been fully elucidated. Here we examine peripheral antinociception elicited by exogenously applied EM-1 and EM-2 and the contribution of EM-containing leukocytes to stress- and corticotropin-releasing factor (CRF)-induced antinociception. To this end, we applied behavioral (paw pressure) testing, radioligand binding, immunohistochemistry, and flow cytometry in rats with unilateral hindpaw inflammation induced with Freund’s adjuvant. EMs injected directly into both hindpaws produced antinociception exclusively in inflamed paws. This was blocked by locally applied μ-receptor-selective (d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH₂) but not κ-receptor-selective (nor-binaltorphimine) antagonists. δ-Receptor antagonists (naltrindole and N,N-diallyl-Tyr-Aib-Aib-Phe-Leu) did not influence EM-1-induced but dose-dependently decreased EM-2-induced antinociception. Antibodies against β-endorphin, methionine-enkephalin, or leucine-enkephalin did not significantly change EM-2-induced antinociception. Both EMs displaced binding of [³H]-[d-Ala²,N-Me-Phe⁴,Gly⁵-ol]enkephalin to μ-receptors in dorsal root ganglia (DRG). Using [³H]-naltrindole or [¹²⁵I]-[d-Pen2,5]-enkephalin, no detectable δ-binding was found in DRG of inflamed hindlimbs. Numerous β-endorphin-containing and fewer EM-1- and EM-2-containing leukocytes were detected in subcutaneous tissue of inflamed paws. Leukocyte-depleting serum decreased the number of immigrating opioid-containing immune cells and attenuated swim stress- and CRF-induced antinociception in inflamed paws. Both forms of antinociception were strongly attenuated by anti-β-endorphin and to a lesser degree by anti-EM-1 and anti-EM-2 antibodies injected into inflamed paws. Together, exogenously applied and immune cell-derived EMs alleviate prolonged inflammatory pain through selective activation of peripheral opioid receptors. Exogenous EM-2 in addition to μ-receptors also activates peripheral δ-receptors, which does not involve actions via other opioid peptides.