Inflammatory hyperalgesia was induced in wild-type, heterozygous and mu-opioid receptor knockout mice after an intraplantar injection of complete Freund's adjuvant. micro-Opioid receptor knockout mice exhibited faster recovery from hyperalgesia as compared to heterozygous (P<0.05) and wild-type (P<0.01) mice. Naloxone restored hyperalgesia in all genotypes. Naltrindole (delta-opioid receptor-selective antagonist) partially restored the hyperalgesia only in mu-opioid receptor knockout mice (P<0.001). Nor-binaltorphimine (kappa-opioid receptor-selective antagonist) had no effect. The mu-opioid receptor-selective agonist, [D-Ala(2), MePhe(4),Gly-ol(5)]enkephalin (DAMGO), reduced the hyperalgesia in heterozygous and wild-type but not in mu-opioid receptor knockout mice while U69,593 ¿(+)-(5alpha,7alpha, 8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-benzeneacetamide, kappa-opioid receptor-selective¿ produced similar effects in all mice. The delta-opioid receptor-selective agonists, [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) and deltorphin ([D-Ala(2)]deltrophin-II), produced significantly greater antihyperalgesia in knockout mice (P<0.05). The findings suggest that mu-opioid receptors may be involved in the persistence of inflammatory hyperalgesia and that a delta-opioid receptor-mediated compensatory mechanism in the absence of the mu-opioid receptor is activated by persistent hyperalgesia.