EFFECTS OF NALTREXONE AND HISTAMINE-ANTAGONISTS ON THE ANTINOCICEPTIVE ACTIVITY OF THE CIMETIDINE ANALOG SKF92374 IN RATS

A recent study showed that SKF92374, a structural analog of the histam ine H-2 receptor antagonist cimetidine, induces antinociception after intraventricular (i.v.t.) administration in the rat. SKF92374 lacked s ignificant activity on H-1 or H-2 receptors, but had weak activity on H-3 receptors. To test the hypothesis that SKF92374-induced antinocice ption is mediated by an action on H-3 receptors, the effects of the H- 3 agonist R-alpha-methylhistamine (RAMH) and the H-3 antagonist thiope ramide (both by i.v.t. administration) were investigated on SKF92374 a ntinociception. SKF92374-induced antinociception was slightly enhanced by thioperamide (30 mu g), but unaffected by a range of doses of RAMH (up to 2 mu g). Furthermore, SKF92374-induced antinociception was not reduced by large doses of systemically-administered antagonists of H- 1 (pyrilamine), H-2 (zolantidine), H-3 (GT-2016), or opioid (naltrexon e) receptors. These findings show that the novel compound SKF92374 ind uces antinociception by a non-opioid mechanism that does not utilize b rain H-1, H-2 or H-3 receptors.