This work aimed to evaluate the potential role of the 5-HT7 receptor in nociception secondary to a sensitizing stimulus in mice. For this purpose, the effects of relevant ligands (5-HT7 receptor agonists: AS-19, MSD-5a, E-55888; 5-HT7 receptor antagonists: SB-258719, SB-269970; 5-HT1A receptor agonist: F-13640; 5-HT1A 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-HT7 receptor agonists used, binding profile and intrinsic efficacy to stimulate cAMP formation in HEK-293F cells expressing the human 5-HT7 receptor were also evaluated. AS-19 and E-55888 were selective for 5-HT7 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-HT7 receptor agonists exerted a clear-cut dose-dependent antinociceptive effect that was prevented by 5-HT7 receptor antagonists, but not by the 5-HT1A receptor antagonist. The order of efficacy (E-55888 > AS-19 > MSD-5a) matched their in vitro efficacy as 5-HT7 receptor agonists. Contrary to agonists, a dose-dependent promotion of mechanical hypersensitivity was observed after administration of 5-HT7 receptor antagonists, substantiating the involvement of the 5-HT7 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-HT7 receptors, and point to a new potential therapeutic use of 5-HT7 receptor agonists in the field of analgesia.
aLaboratorios Esteve, Department of Pharmacology, Av. Mare de Déu de Montserrat, 221, 08041 Barcelona, Spain
bUMR 677 INSERM/UPMC, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, 91 Boulevard de l’hôpital, 75634 Paris Cedex 13, France
cDepartmento de Farmacología e Instituto de Neurociencias, Facultad de Medicina, Universidad de Granada, Av. de Madrid, 11, 18012 Granada, Spain
*Corresponding author. Tel.: +34 93 4466244; fax: +34 93 4466220.
Received April 29, 2008
Received in revised form October 20, 2008
Accepted November 10, 2008.