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Serotonin 5-HT2A receptor involvement and Fos expression at the spinal level in vincristine-induced neuropathy in the rat

Thibault, Karinea,b,1; Van Steenwinckel, Juliettea,1; Brisorgueil, Marie-Jeannea; Fischer, Jacquelinea; Hamon, Michelc; Calvino, Bernardb; Conrath, Mariea,*

doi: 10.1016/j.pain.2008.09.006
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We recently showed that peripheral and spinal 5-HT2A receptors (5-HT2AR) are involved in a rodent model of neuropathy induced by a nucleoside analogue reverse transcriptase inhibitor. In this paper, we show that 5-HT2AR are also involved in neuropathy induced by an anti-neoplasic drug, vincristine. Vincristine-treated rats (0.1 mg/kg, daily i.p. administration for two 5-day cycles) developed thermal allodynia and mechanical hypersensitivity, which decreased in a dose-related manner after epidural injection a 5-HT2A receptor antagonist. Moreover, 5-HT2A−/− mice did not develop vincristine-induced neuropathy contrarily to their 5-HT2A+/+ littermates. In vincristine-treated rats, the number of nociceptive dorsal root ganglion cells expressing the 5-HT2AR was increased by 38%, and 5-HT2AR immunolabelling was enhanced in layers I–IV of the dorsal horn. At the EM level, a 76.3% increase in the density of 5-HT2AR immunopositive axon terminals within superficial layers of the dorsal horn was noted after vincristine treatment. Immunocytochemical study of Fos expression in vincristine-treated rats revealed a significant increase in the number of Fos-positive neurons not only in regions where nociceptive fibres terminate superficial (I–II) and deep layers (V–VI) of the spinal cord, but also in intermediate layers, suggesting that Aβ fibres could be involved in the spinal sensitization observed in this model. Double labelling experiments showed that Fos-positive neurons were endowed with 5-HT2AR immunolabelling in the dorsal horn of vincristine-treated rats. These data provide support to the idea that, in vincristine-induced neuropathy, 5-HT2AR are involved in the sensitization of peripheral nociceptors and spinal nociceptive processing.

aNeurobiologie des Signaux Intercellulaires, CNRS, UMR 7101, Université Pierre et Marie Curie-Paris 6, 7 Quai St. Bernard, 75252 Paris Cedex 05, France

bCNRS UMR 7637, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France

cINSERM UMR 677, Université Pierre et Marie Curie-Paris 6, Faculté de Médecine, site Pitié-Salpêtrière, 91 boulevard de l’Hôpital, 75634 Paris Cedex 13, France

*Corresponding author. Tel.: +33 144273272; fax: +33 144272508.

E-mail: marie.conrath@snv.jussieu.fr

1These authors equally contributed to this work.

Submitted May 13, 2008; revised July 30, 2008; accepted September 3, 2008.

© 2008 Lippincott Williams & Wilkins, Inc.
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