Evidence suggests that the ATP-sensitive K+ channels are important in the peripheral antinociceptive effect of diclofenac. Combinations of nonsteroidal anti-inflammatory drugs (NSAIDs) with other different drugs are currently used in clinical practice to increase the analgesic efficacy and to reduce adverse events. We evaluated the effect of the combination of diclofenac and the activator of K+ channels pinacidil in the formalin test. Female Wistar rats (180-200 g) were injected in the dorsal surface of the right hind paw with 50 microl of formalin (1%). Nociception was quantified as the number of flinches of the injected paw during the next 60 mins, while reduction of flinches was considered antinociception. Ipsilateral, but not contralateral, pretreatment with diclofenac (25-200 microg/paw) or pinacidil (5-50 microg/paw) significantly reduced, in a dose-dependent manner the formalin-induced flinching behavior during the second phase of the test. To determine if pinacidil was able to increase the effect of diclofenac, noneffective increasing doses of pinacidil were coadministered with an ineffective dose of diclofenac (25 microg). The local co-administration of pinacidil and diclofenac produced a significant reduction in the number of flinches during phase 2, but not during phase 1 of the test compared to the effect of either drug alone. In conclusion, the combination of individually ineffective doses of diclofenac and pinacidil produce an antinociceptive effect in the formalin test. In addition, pinacidil increased the action of diclofenac, probably through the activation of K+ channels.