4.6 Article

Transient, 5-HT2B receptor-mediated facilitation in neuropathic pain: Up-regulation of PKCγ and engagement of the NMDA receptor in dorsal horn neurons

Journal

PAIN
Volume 154, Issue 9, Pages 1865-1877

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1016/j.pain.2013.06.009

Keywords

Neuropathic pain; Serotonin; Electrophysiology; Evoked potentials; Synaptic plasticity

Funding

  1. Government of the Basque Country under program SAIOTEK [SA-2010/00110]
  2. Ayudas a Grupos de Investigacion del Sistema Universitario Vasco

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Spinal nociception can be facilitated by 5-HT2 receptors in neuropathic pain. We investigated the involvement of glutamate receptors in dorsal neuron hyperexcitation that is promoted by 5-HT2B receptor (5-HT2BR) after spinal nerve ligation (SNL) in the rat. Augmentation of C-fiber-evoked potentials by spinal superfusion with 5-HT2BR agonist BW 723C86 in nerve-ligated rats was impeded by co-administration of NMDA receptor (NMDAR) antagonist D-AP5, but not by mGluR1/5 antagonist AIDA or mGluR2/3 antagonist LY 341495. Evoked potentials were increased by cis-ACPD in nerve-injured rats, irrespective of simultaneous 5-HT2BR blockade by SB204741. In uninjured rats, NMDAR agonist cis-ACPD enhanced evoked potentials in the presence of BW 723C86 but not if administered alone or during exposure to protein kinase C gamma (PKC gamma) inhibitor peptide. Triple immunofluorescence labelings revealed co-localization of NMDAR and 5-HT2BR in PKC gamma-expressing perikarya in lamina II neurons. As a result of SNL, PKC gamma was transiently and bilaterally up-regulated in synaptic fraction from dorsal horn homogenates, peaking at day 2 and returning to basal levels by day 9. Chronic blockade of 5-HT2BR with selective antagonist SB 204741 after SNL bilaterally decreased the following: (i) PKC gamma up-regulation in synaptic fraction, (ii) phosphorylation of NMDAR subunit NR1 (serine 889) in synaptic fraction, and (iii) co-localization of both PKC gamma and phosphorylated NR1 with postsynaptic marker PSD-95. Chronic delivery of SB 204741 bilaterally attenuated thermal and mechanical allodynia occurring after SNL, particularly at day 2 post injury. These findings suggest that transient activation of the PKC gamma/NMDAR pathway is critically involved in 5-HT2BR-mediated facilitation in the SNL model of neuropathic pain. (c) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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