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: Alex Brenchat, Luz Romero, Mónica García, Marta Pujol, Javier Burgueño, Antoni Torrens, Michel Hamon, José Manuel Baeyens, Helmut Buschmann, Daniel Zamanillo, José Miguel Vela
• Journal: Pain (Pain) Vol. 141 Issue 3 Pg. 239-247 (Feb 2009) ISSN: 1872-6623 [Electronic] United States
• PMID: 19118950 (Publication Type: Journal Article)

Chemical References

• Pyrazoles
• Receptors, Serotonin
• Serotonin Agents
• dimethyl-(2-(3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethyl)amine dihydrochloride
• serotonin 7 receptor
• Cyclic AMP
• Capsaicin

Topics

• Animals
• Capsaicin
• Cell Line, Transformed
• Cyclic AMP (metabolism)
• Dose-Response Relationship, Drug
• Drug Interactions
• Humans
• Hyperalgesia (chemically induced, drug therapy)
• Male
• Mice
• Pain Measurement
• Pain Threshold (drug effects)
• Protein Binding (drug effects)
• Pyrazoles (pharmacology)
• Reaction Time (drug effects)
• Receptors, Serotonin (drug effects, metabolism)
• Serotonin Agents (pharmacology)