title: Histamine H3 receptor activation potentiates peripheral opioid-mediated antinociception: substance P role in peripheral inflammation in mice.
abstract: Opioids provide effective analgesia in adult patients with painful inflammatory diseases. The proposed mechanism of action is the activation of peripheral opioid receptors, which may be up-regulated in such conditions. Here, by using a chronic inflammation model, namely subplantar injection of Complete Freund's adjuvant, we show a peripheral synergistic interaction between the histamine H(3) receptor agonist R-(alpha)-methylhistamine and fentanyl on the inhibition of thermal hyperalgesia and of peripheral substance P accumulation. Firstly, dose-related effects obtained for the subplantar antinociceptive effect of fentanyl (0.05-1 microg) in the presence of a fixed dose of R-(alpha)-methylhistamine (12.5 microg) showed a shift to the left when compared to that obtained with fentanyl alone. In a similar way, the subcutaneous administration of fentanyl (0.005-0.1mg/kg) plus a fixed dose of R-(alpha)-methylhistamine (0.5mg/kg) induced a supra additive effect on the inhibition of substance P accumulation in the hind-paw skin of inflamed mice. Interestingly, when a neurokinin-1 receptor antagonist was co-administered, the antinociceptive effects of the combined treatment were potentiated. The peripheral adjuvant effect of R-(alpha)-methylhistamine on fentanyl antinociception and inhibition of substance P accumulation was also demonstrated by means of opioid and histamine H(3) receptors selective antagonists: first, naloxone blockade of fentanyl-mediated effects were partially reversed by co-administration of R-(alpha)-methylhistamine, and second, thioperamide partially antagonised the combined R-(alpha)-methylhistamine/fentanyl effects. Overall, our results clearly show that R-(alpha)-methylhistamine enhances fentanyl effects at peripheral sites, and that the control of substance P levels might be one of the mechanisms responsible of such interaction.
authors.affiliation: Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, Universitat de Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain. vfernandez@ub.edu
authors.forename: Víctor
authors.initials: V
authors.lastname: Fernández-Dueñas
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.forename: Jorge
authors.initials: J
authors.lastname: Gandía
authors.forename: Sílvia
authors.initials: S
authors.lastname: Sánchez
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Planas
authors.forename: Raquel
authors.initials: R
authors.lastname: Poveda
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005283:Fentanyl / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005620:Freund's Adjuvant; D017442:Histamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D008761:Methylhistamines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*
chemical_list: D000700:Analgesics; D017442:Histamine Agonists; D008761:Methylhistamines; D010880:Piperidines; D018100:Receptors, Histamine H3; D013373:Substance P; D009270:Naloxone; D005620:Freund's Adjuvant; C052075:thioperamide; D005283:Fentanyl