Pharmacological activation of 5-HT<inf>7</inf> receptors reduces nerve injury-induced mechanical and thermal hypersensitivity

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

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57 Citations (Scopus)

Abstract

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. © 2010 International Association for the Study of Pain.
Original languageEnglish
Pages (from-to)483-494
JournalPain
Volume149
Issue number3
DOIs
Publication statusPublished - 1 Jun 2010

Keywords

  • Allodynia
  • Hyperalgesia
  • Hypersensitivity
  • Neuropathic pain
  • Pain
  • Serotonin 5-HT receptor 7
  • Spinal cord

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