Analgesic effects of cannabimimetic compounds have been known to be related to their central effects. Cannabinoid receptors also exist in the periphery but their role in pain perception has been remained to be clarified. Therefore, we assessed topical antinociceptive effects of WIN 55, 212-2, a mixed CB(1) and CB(2) receptors agonist, in mice using tail-flick test. Immersion of the tail of mouse into the WIN 55, 212-2 solution produced dose-dependent antinociception. This antinociceptive activity was limited to the portion of the tail exposed to WIN 55, 212-2. The antinociceptive response was dependent on duration of exposure to WIN 55, 212-2 solution. The topical antinociceptive effects of WIN 55, 212-2 were dose dependently blocked by topical pretreatment of CB(1) receptor-selective antagonist, AM 251. Thus, topical antinociceptive action of WIN 55, 212-2 involve CB(1) receptors. Intrathecal (i.th.) administration of WIN 55, 212-2 produced a dose-dependent antinociceptive effect. Interestingly, ineffective i.th. doses of WIN 55, 212-2 produced a marked antinociception when combined with topical application of WIN 55, 212-2 and topical antinociceptive effect was potentiated. The dose-response curve of i.th. WIN 55, 212-2 was shifted to the left 15-fold by topical WIN 55, 212-2. This finding suggests that there is an antinociceptive synergy between peripheral and spinal sites of cannabinoid action and it also implicates that local activation of cannabinoid system may regulate pain initiation in cutaneous tissue. Our findings support that cannabinoid system participates in buffering the emerging pain signals at the peripheral sites in addition to their spinal and supraspinal sites of action. In addition, an antinociceptive synergy between topical and spinal cannabinoid actions exists. These results also indicate that topically administered cannabinoid agonists may reduce pain without the dysphoric side effects and abuse potential of centrally acting cannabimimetic drugs.