title: 5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice.
abstract: This work aimed to evaluate the potential role of the 5-HT(7) receptor in nociception secondary to a sensitizing stimulus in mice. For this purpose, the effects of relevant ligands (5-HT(7) receptor agonists: AS-19, MSD-5a, E-55888; 5-HT(7) receptor antagonists: SB-258719, SB-269970; 5-HT(1A) receptor agonist: F-13640; 5-HT(1A) receptor antagonist: WAY-100635) were assessed on capsaicin-induced mechanical hypersensitivity, a pain behavior involving hypersensitivity of dorsal horn neurons (central sensitization). For the 5-HT(7) receptor agonists used, binding profile and intrinsic efficacy to stimulate cAMP formation in HEK-293F cells expressing the human 5-HT(7) receptor were also evaluated. AS-19 and E-55888 were selective for 5-HT(7) receptors. E-55888 was a full agonist whereas AS-19 and MSD-5a behaved as partial agonists, with maximal effects corresponding to 77% and 61%, respectively, of the cAMP response evoked by the full agonist 5-HT. Our in vivo results revealed that systemic administration of 5-HT(7) receptor agonists exerted a clear-cut dose-dependent antinociceptive effect that was prevented by 5-HT(7) receptor antagonists, but not by the 5-HT(1A) receptor antagonist. The order of efficacy (E-55888>AS-19>MSD-5a) matched their in vitro efficacy as 5-HT(7) receptor agonists. Contrary to agonists, a dose-dependent promotion of mechanical hypersensitivity was observed after administration of 5-HT(7) receptor antagonists, substantiating the involvement of the 5-HT(7) receptor in the control of capsaicin-induced mechanical hypersensitivity. These findings suggest that serotonin exerts an inhibitory role in the control of nociception through activation of 5-HT(7) receptors, and point to a new potential therapeutic use of 5-HT(7) receptor agonists in the field of analgesia.
authors.affiliation: Laboratorios Esteve, Department of Pharmacology, Av. Mare de Déu de Montserrat, 221, 08041 Barcelona, Spain UMR 677 INSERM/UPMC, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, 91 Boulevard de l'hôpital, 75634 Paris Cedex 13, France Departmento de Farmacología e Instituto de Neurociencias, Facultad de Medicina, Universidad de Granada, Av. de Madrid, 11, 18012 Granada, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Brenchat
authors.forename: Luz
authors.initials: L
authors.lastname: Romero
authors.forename: Mónica
authors.initials: M
authors.lastname: García
authors.forename: Marta
authors.initials: M
authors.lastname: Pujol
authors.forename: Javier
authors.initials: J
authors.lastname: Burgueño
authors.forename: Antoni
authors.initials: A
authors.lastname: Torrens
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Baeyens
authors.forename: Helmut
authors.initials: H
authors.lastname: Buschmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Zamanillo
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vela
mesh_terms: D000818:Animals; D002211:Capsaicin; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy; D008297:Male; D051379:Mice; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology
chemical_list: D011720:Pyrazoles; D011985:Receptors, Serotonin; D018490:Serotonin Agents; C540144:dimethyl-(2-(3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethyl)amine dihydrochloride; C104425:serotonin 7 receptor; D000242:Cyclic AMP; D002211:Capsaicin