The involvement of the 5-HT7 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-HT7 receptor participates in some modulatory control of nerve injury-evoked mechanical hypersensitivity and thermal (heat) hyperalgesia in mice. Activation of 5-HT7 receptors by systemic administration of the selective 5-HT7 receptor agonist AS-19 (1 and 10 mg/kg) exerted a clear-cut reduction of mechanical and thermal hypersensitivities that were reversed by co-administering the selective 5-HT7 receptor antagonist SB-258719. Interestingly, blocking of 5-HT7 receptors with SB-258719 (2.5 and 10 mg/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-HT7 receptor agonist was maintained after repeated systemic administration: no tolerance to the antiallodynic and antihyperalgesic effects was developed following treatment with the selective 5-HT7 receptor agonist E-57431 (10 mg/kg) twice daily for 11 days. The 5-HT7 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-HT7 receptor agonists. In addition, a significant increase of 5-HT7 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-HT7 receptor subtype is involved in the control of pain and point to a new potential use of 5-HT7 receptor agonists for the treatment of neuropathic pain.
aDepartment of Pharmacology, Esteve, Av. Mare de Déu de Montserrat, 221, 08041 Barcelona, Spain
bLaboratory of Neuropharmacology, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Doctor Aguader, 88, 08003 Barcelona, Spain
cUMR 894 INSERM/UPMC, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, 91 Boulevard de l'hôpital, 75634 Paris Cedex 13, France
*Corresponding author. Tel.: +34 93 4466244; fax: +34 93 4466220.
Submitted June 18, 2009; revised January 16, 2010; accepted March 8, 2010.