Pharmacological activation of 5-HT7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity.

Abstract

The involvement of the 5-HT(7) receptor in nociception and pain, particularly chronic pain (i.e., neuropathic pain), has been poorly investigated. In the present study, we examined whether the 5-HT(7) receptor participates in some modulatory control of nerve injury-evoked mechanical hypersensitivity and thermal (heat) hyperalgesia in mice. Activation of 5-HT(7) receptors by systemic administration of the selective 5-HT(7) receptor agonist AS-19 (1 and 10mg/kg) exerted a clear-cut reduction of mechanical and thermal hypersensitivities that were reversed by co-administering the selective 5-HT(7) receptor antagonist SB-258719. Interestingly, blocking of 5-HT(7) receptors with SB-258719 (2.5 and 10mg/kg) enhanced mechanical (but not thermal) hypersensitivity in nerve-injured mice and induced mechanical hypersensitivity in sham-operated mice. Effectiveness of the treatment with a 5-HT(7) receptor agonist was maintained after repeated systemic administration: no tolerance to the antiallodynic and antihyperalgesic effects was developed following treatment with the selective 5-HT(7) receptor agonist E-57431 (10mg/kg) twice daily for 11 days. The 5-HT(7) receptor co-localized with GABAergic cells in the dorsal horn of the spinal cord, suggesting that the activation of spinal inhibitory GABAergic interneurons could contribute to the analgesic effects of 5-HT(7) receptor agonists. In addition, a significant increase of 5-HT(7) receptors was found by immunohistochemistry in the ipsilateral dorsal horn of the spinal cord after nerve injury, suggesting a "pain"-triggered regulation of receptor expression. These results support the idea that the 5-HT(7) receptor subtype is involved in the control of pain and point to a new potential use of 5-HT(7) receptor agonists for the treatment of neuropathic pain.

• Authors: Alex Brenchat, Xavier Nadal, Luz Romero, Sergio Ovalle, Asunción Muro, Ricard Sánchez-Arroyos, Enrique Portillo-Salido, Marta Pujol, Ana Montero, Xavier Codony, Javier Burgueño, Daniel Zamanillo, Michel Hamon, Rafael Maldonado, José Miguel Vela
• Journal: Pain (Pain) Vol. 149 Issue 3 Pg. 483-494 (Jun 2010) ISSN: 1872-6623 [Electronic] United States
• PMID: 20399562 (Publication Type: Journal Article)

Chemical References

• AS 19 compound
• Pyrazoles
• Receptors, Serotonin
• Serotonin Receptor Agonists
• Tetrahydronaphthalenes
• serotonin 7 receptor

Topics

• Analgesia (methods)
• Animals
• Disease Models, Animal
• Hyperalgesia (drug therapy, metabolism, physiopathology)
• Male
• Mice
• Pain Measurement (methods)
• Pain Threshold (drug effects, physiology)
• Peripheral Nervous System Diseases (drug therapy, metabolism, physiopathology)
• Pyrazoles (pharmacology)
• Receptors, Serotonin (metabolism, physiology)
• Serotonin Receptor Agonists (pharmacology)
• Tetrahydronaphthalenes (pharmacology)
• Treatment Outcome