A recent study showed that SKF92374, a structural analog of the histamine H2 receptor antagonist cimetidine, induces antinociception after intraventricular (i.v.t.) administration in the rat. SKF92374 lacked significant activity on H1 or H2 receptors, but had weak activity on H3 receptors. To test the hypothesis that SKF92374-induced antinociception is mediated by an action on H3 receptors, the effects of the H3 agonist R-alpha-methylhistamine (RAMH) and the H3 antagonist thioperamide (both by i.v.t. administration) were investigated on SKF92374 antinociception. SKF92374-induced antinociception was slightly enhanced by thioperamide (30 microg), but unaffected by a range of doses of RAMH (up to 2 microg). Furthermore, SKF92374-induced antinociception was not reduced by large doses of systemically-administered antagonists of H1 (pyrilamine), H2 (zolantidine), H3 (GT-2016), or opioid (naltrexone) receptors. These findings show that the novel compound SKF92374 induces antinociception by a non-opioid mechanism that does not utilize brain H1, H2 or H3 receptors.