The antinociceptive potency of nociceptin/orphanin FQ, an opioid-like orphan receptor agonist, was examined using the tail-flick test and the formalin-induced nociception test in diabetic mice. Nociceptin/orphanin FQ, at doses of 0.1 to 10 nmol, intrathecal (i.t.), produced a marked and dose-dependent inhibition of the tail-flick response in both non-diabetic and diabetic mice. The antinociceptive effect of nociceptin/orphanin FQ in the tail-flick test in diabetic mice was greater than that in non-diabetic mice. The antinociceptive effect of nociceptin/orphanin FQ was not antagonized by pretreatment with either beta-funaltrexamine, a selective mu-opioid receptor antagonist, naltrindole, a selective delta-opioid receptor antagonist, or nor-binaltorphimine, a selective kappa-opioid receptor antagonist. The antinociceptive effects of nociceptin/orphanin FQ in diabetic, but not in non-diabetic mice, were abolished when mice were pretreated with capsaicin i.t. 24 h before testing. In the formalin test, nociceptin/orphanin FQ also produced a marked and dose-dependent antinociceptive effect on the first-phase response, but not the second phase-response, in both diabetic and non-diabetic mice. Furthermore, nociceptin/orphanin FQ significantly and dose-dependently reduced the flinching responses to i.t.-administered substance P in diabetic mice, but not in non-diabetic mice. The results of the present experiments clearly indicate that the antinociceptive potency of nociceptin/orphanin FQ is significantly greater in diabetic mice than in non-diabetic mice. Furthermore, the results of this study suggest that the reduction of substance P-mediated nociceptive transmission in the spinal cord may be responsible for the antinociceptive effect of nociceptin/orphanin FQ.