Disrupting 5-HT Receptor/PDZ Protein Interactions Reduces Hyperalgesia and Enhances SSRI Efficacy in Neuropathic Pain

• Published in: Molecular therapy 2010-08, Vol.18 (8), p.1462-1470
• Main Authors: Pichon, Xavier, Wattiez, Anne S, Becamel, Carine, Ehrlich, Ingrid, Bockaert, Joel, Eschalier, Alain, Marin, Philippe, Courteix, Christine
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Chromatography, Affinity; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - pathology; Electrophoresis, Gel, Two-Dimensional; Fluoxetine - therapeutic use; Hyperalgesia - drug therapy; Immunoprecipitation; Male; PDZ Domains - physiology; Protein Binding - drug effects; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A - metabolism; Serotonin Uptake Inhibitors - therapeutic use; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2010.101

Antidepressants are one of the first-line treatments for neuropathic pain. Despite the influence of serotonin (5-hydroxytryptamine, 5-HT) in pain modulation, selective serotonin reuptake inhibitors (SSRIs) are less effective than tricyclic antidepressants. Here, we show, in diabetic neuropathic rats, an alteration of the antihyperalgesic effect induced by stimulation of 5-HT(2A) receptors, which are known to mediate SSRI-induced analgesia. 5-HT(2A) receptor density was not changed in the spinal cord of diabetic rats, whereas postsynaptic density protein-95 (PSD-95), one of the PSD-95/disc large suppressor/zonula occludens-1 (PDZ) domain containing proteins interacting with these receptors, was upregulated. Intrathecal injection of a cell-penetrating peptidyl mimetic of the 5-HT(2A) receptor C-terminus, which disrupts 5-HT(2A) receptor-PDZ protein interactions, induced an antihyperalgesic effect in diabetic rats, which results from activation of 5-HT(2A) receptors by endogenous 5-HT. The peptide also enhanced antihyperalgesia induced by the SSRI fluoxetine. Its effects likely resulted from an increase in receptor responsiveness, because it revealed functional 5-HT(2A) receptor-operated Ca(2+) responses in neurons, an effect mimicked by knockdown of PSD-95. Hence, 5-HT(2A) receptor/PDZ protein interactions might contribute to the resistance to SSRI-induced analgesia in painful diabetic neuropathy. Disruption of these interactions might be a valuable strategy to design novel treatments for neuropathic pain and to increase the effectiveness of SSRIs.