Journal
PAIN
Volume 153, Issue 7, Pages 1418-1425Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1016/j.pain.2012.03.017
Keywords
Electrophysiology; Immunocytochemistry; Opioid receptors; Protein kinase C; Rat; Serotonin receptors; Spinal cord; Spinal field potentials
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Funding
- Government of the Basque Country [SA-2010/00110]
- Ayudas a Grupos de Investigacion del Sistema Universitario Vasco
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Opioid analgesia is compromised by intracellular mediators such as protein kinase C (PKC). The phosphatidylinositol hydrolysis-coupled serotonin receptor 5-HT2 is ideally suited to promote PKC activation. We test the hypothesis that 5-HT2A and 5-HT2B receptors, which have been previously shown to become pro-excitatory after spinal nerve ligation (SNL), can negatively influence the ability of opioids to depress spinal excitation evoked by noxious input. Spinal superfusion with (100 nM) mu-opioid receptor (MOR)-agonist DAMGO significantly depressed C fiber-evoked spinal field potentials. Simultaneous administration of subclinical 5-HT2AR antagonist 4F 4PP (100 nM) or 5-HT2BR antagonist SB 204741 (100 nM) significantly reduced the IC50 value for DAMGO in nerve-ligated rats (97.56 nM +/- 1.51 and 1.20 nM +/- 1.28 respectively, relative to 104 nM +/- 1.08 at the baseline condition), but not in sham-operated rats. Both antagonists failed to alter depression induced by delta-opioid receptor (DOR)-agonist D-ala2-deltorphin II after SNL as well as in the sham condition. Western blot analysis of dorsal horn homogenates revealed bilateral upregulation of 5-HT2AR and 5-HT2BR protein band densities after SNL. As assessed from double immunofluorescence labeling for confocal laser scanning microscopy, scarce dorsal horn cell processes showed co-localization color overlay for 5-HT2AR/MOR, 5-HT2BR/MOR, 5-HT2AR/DOR, or 5-HT2BR/DOR in sham-operated rats. Intensity correlation-based analyses showed significant increases in 5HT2AR/MOR and 5- HT2BR/MOR co-localizations after SNL. These results indicate that plasticity of spinal serotonergic neurotransmission can selectively reduce spinal MOR mechanisms via 5-HT2A and 5-HT2B receptors, including upregulation of the latter and increased expression in dorsal horn neurons containing MOR. (C) 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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