We have reported previously that the dipeptidyl peptidase IV inhibitor Ile-Pro-Ile had an antihyperalgesic action in rats when given intrathecally in the carrageenan-induced hyperalgesia, as detected by the RandallSelitto test. Vildagliptin, a non-peptide inhibitor of the same enzyme, which is already on the market as an euglycemic agent in diabetics, has a slightly more potent and more sustained antihyperalgesic effect in the same test when given by the same route. The action of 3 nmol/rat vildagliptin could be antagonized by subcutaneous naltrexone (0.5 mg/kg) pretreatment, or by intrathecally co-administered specific antiserum to endomorphin-2. Thus, the antihyperalgesia by vildagliptin, similarly to Ile-Pro-Ile, was opioid receptor-mediated and could be attributed to the promotion of endomorphin-2 generation in rat spinal cord dorsal horn. Furthermore, vildagliptin (1 mg/kg) is a potent antihyperalgesic also when given subcutaneously.