We examined the antinociceptive effect of intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administered of interferon-alpha (IFN-${alpha}$) using the tail-flick analgesic test in mice. IFN-${alpha}$ administered i.c.v. but not i.t. showed an antinociceptive effect in a dose-dependent manner (0.05 - 5 ${mu}g$). To examine the possible interaction with brain opioid system, IFN-${alpha}$ was co-treated with either ${eta}$-endorphin or morphine. Combined i.c.v. treatment of IFN-${alpha}$ (0.5 ${mu}g$) with ${eta}$-endorphin (0.125 ${mu}g$) caused a synergistic antinociceptive effect. And also, the synergistic interaction maintained at least for 60 min after the co-treatment of IFN-${alpha}$ and ${eta}$-endorphin. However, the combined treatment of i.t. IFN-${alpha}$ with i.c.v. ${eta}$-endorphin showed neither an additive nor a synergistic antinociceptive profile. The i.c.v. co-treatment of IFN-${alpha}$ with morphine (0.2 ${mu}g$) showed an additive antinociceptive effect only. The i.t. administered IFN-${alpha}$ did not show any additive antinociceptive effect when morphine was administered i.c.v. simultaneously. Taken together, our results suggest that supraspinally co-administered IFN-${alpha}$ and ${eta}$-endorphin may produce antinociception synergistically via interaction of IFN-${alpha}$ with supraspinal ${eta}$-endorphin sensitive opioid receptors.