Synergistic interaction between fentanyl and the histamine H3 receptor agonist R-(α)-methylhistamine, on the inhibition of nociception and plasma extravasation in mice

Here we report a synergistic interaction between fentanyl and the histamine H3 receptor agonist R-(α)-methylhistamine on the inhibition of nociception and plasma extravasation in mice. Chronic inflammation was induced by subplantar injection of Complete Freund's Adjuvant into the right hind paw, and the effect of the drugs was evaluated 7 days later. Nociception and plasma extravasation were assessed by hot-plate and Evans blue tests respectively. Subcutaneous administration of fentanyl (0.01–0.1 mg/kg) induced dose-related anti-nociceptive and anti-extravasation effects (Emax = 100% and 62%, respectively). R-(α)-methylhistamine administration (0.3–3 mg/kg) showed a dose-related inhibitory effect on extravasation (Emax = 65%) but not on nociception. To analyze possible interaction between these two drugs, a dose–response curve to fentanyl plus a fixed dose of R-(α)-methylhistamine (0.5 mg/kg) was obtained. The dose–response curve for the combined treatment showed a shift to the left compared with that for fentanyl alone. Our results confirm that fentanyl and R-(α)-methylhistamine interact in a synergic way, inhibiting nociception and plasma extravasation.