PT  - JOURNAL ARTICLE
AU  - B Y Li
AU  - J W Nalwalk
AU  - L A Barker
AU  - P Cumming
AU  - M E Parsons
AU  - L B Hough
TI  - Characterization of the antinociceptive properties of cimetidine and a structural analog.
DP  - 1996 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 500--508
VI  - 276
IP  - 2
4099  - http://jpet.aspetjournals.org/content/276/2/500.short
4100  - http://jpet.aspetjournals.org/content/276/2/500.full
SO  - J Pharmacol Exp Ther1996 Feb 01; 276
AB  - The antinociceptive and pharmacological properties of the H2 receptor antagonist cimetidine and a novel cimetidine analog, SKF92374, were characterized. On both the hot-plate and tail-flick nociceptive tests, cimetidine and SKF92374 induced complete, dose-related analgesic responses when injected into the lateral ventricle of rats. SKF92374 showed strong similarities to cimetidine in analgesic efficacy, slope of dose-response curves and chemical structure, suggesting that these compounds share a common analgesic mechanism. In contrast, histamine induced submaximal antinociceptive effects, and the H3 antagonist thioperamide, a known HA-releasing drug, had little or no analgesic effects. Compared with cimetidine, SKF92374 showed very weak activity (400-fold lower affinity) on H2 receptors in vitro (isolated guinea pig atrium) and in vivo (rat gastric secretion). In addition, SKF92374 (100 microM) had neither agonist nor antagonist action on guinea pig ileum H1 receptors. SKF92374 was also a weak competitive antagonist of N alpha-methylhistamine-induced inhibition of electrically induced contractions of the guinea pig ileum (Kd = 5.2 microM), an H3 receptor-mediated response. Autoradiographic binding assays in guinea pig brain confirmed a weak antagonism of H3 receptors by SKF92374. The compound (up to 10 microM) also had no effect on unpurified rat brain histamine N-methyltransferase activity. These results support the hypothesis that cimetidine induces analgesia by a novel brain mechanism unrelated to H1, H2 or H3 receptors.