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Pamabrom is a diuretic that is effective in treating premenstrual syndrome and primary dysmenorrhea. The aim of this study was to examine the effect of metformin and modulators of the opioid receptor-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-[K.sup.+] channel pathway on the local antinociception induced by pamabrom. The rat paw 1% formalin test was used to assess the effects. Rats were treated with local administration of pamabrom (200-800 [micro]g/paw) or indomethacin (200800 [micro]g/paw). The antinociception of pamabrom or indomethacin was evaluated with and without the local pretreatment of the blockers. Local administration of pamabrom and indomethacin produced dose-dependent antinociception during the second phase of the test. Local pretreatment of the paws with naloxone (50 [micro]g/paw), L-nitro-arginine methyl ester (10-100 [micro]g/paw), or 1H-(1,2,4)-oxadiazolo[4,2-a]quinoxalin-1-one (10-100 [micro]g/paw) reverted the antinociception induced by local pamabrom, but not of indomethacin. Similarly, the [K.sup.+] channel blockers glibenclamide, glipizide, 4-aminopyridine, tetraethylammonium, charybdotoxin, or apamin reverted the pamabrom-induced antinociception, but not of indomethacin. Metformin significantly blocked the antinociception of pamabrom and indomethacin. Our data suggest that pamabrom could activate the opioid receptor-NO-cGMP-[K.sup.+] channel pathway to produce its peripheral antinociception in the formalin test. Likewise, a biguanide-dependent mechanism could be activated by pamabrom and indomethacin to generate antinociception. Key words: pamabrom, antinociception, nitric oxide, cGMP, opioid receptor, metformin, [K.sup.+] channels, Introduction Premenstrual syndrome (PMS) is a disorder of cyclic recurrence that encompasses a set of repetitive symptoms, which can occur a few days before menstruation and decrease or disappear with [...]