title: 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.affiliation: Department of Pharmacology, Esteve, Av. Mare de Déu de Montserrat, 221, 08041 Barcelona, Spain Laboratory of Neuropharmacology, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Doctor Aguader, 88, 08003 Barcelona, Spain UMR 894 INSERM/UPMC, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, 91 Boulevard de l'hôpital, 75634 Paris Cedex 13, France.
authors.forename: Alex
authors.initials: A
authors.lastname: Brenchat
authors.forename: Xavier
authors.initials: X
authors.lastname: Nadal
authors.forename: Luz
authors.initials: L
authors.lastname: Romero
authors.forename: Sergio
authors.initials: S
authors.lastname: Ovalle
authors.forename: Asunción
authors.initials: A
authors.lastname: Muro
authors.forename: Ricard
authors.initials: R
authors.lastname: Sánchez-Arroyos
authors.forename: Enrique
authors.initials: E
authors.lastname: Portillo-Salido
authors.forename: Marta
authors.initials: M
authors.lastname: Pujol
authors.forename: Ana
authors.initials: A
authors.lastname: Montero
authors.forename: Xavier
authors.initials: X
authors.lastname: Codony
authors.forename: Javier
authors.initials: J
authors.lastname: Burgueño
authors.forename: Daniel
authors.initials: D
authors.lastname: Zamanillo
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vela
mesh_terms: D000698:Analgesia / Q000379:methods*; D000818:Animals; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D011720:Pyrazoles / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000378:metabolism* / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: C505862:AS 19 compound; D011720:Pyrazoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; C104425:serotonin 7 receptor
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