TY - JOUR
T1 - Pharmacological activation of 5-HT7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity
AU - Brenchat, Alex
AU - Nadal, Xavier
AU - Romero, Luz
AU - Ovalle, Sergio
AU - Muro, Asunción
AU - Sánchez-Arroyos, Ricard
AU - Portillo-Salido, Enrique
AU - Pujol, Marta
AU - Montero, Ana
AU - Codony, Xavier
AU - Burgueño, Javier
AU - Zamanillo, Daniel
AU - Hamon, Michel
AU - Maldonado, Rafael
AU - Vela, José Miguel
PY - 2010/6/1
Y1 - 2010/6/1
N2 - 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.
AB - 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.
KW - Allodynia
KW - Hyperalgesia
KW - Hypersensitivity
KW - Neuropathic pain
KW - Pain
KW - Serotonin 5-HT receptor 7
KW - Spinal cord
U2 - 10.1016/j.pain.2010.03.007
DO - 10.1016/j.pain.2010.03.007
M3 - Article
VL - 149
SP - 483
EP - 494
JO - Pain
JF - Pain
SN - 0304-3959
IS - 3
ER -