Disrupting 5-HT2A Receptor/PDZ Protein Interactions Reduces Hyperalgesia and Enhances SSRI Efficacy in Neuropathic Pain |
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Authors: | Xavier Pichon Anne S Wattiez Carine Becamel Ingrid Ehrlich Joel Bockaert Alain Eschalier Philippe Marin Christine Courteix |
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Affiliation: | 1. Clermont Université, Université d''Auvergne, Pharmacologie fondamentale et clinique de la Douleur, Clermont-Ferrand, France;2. Inserm, U766, Clermont-Ferrand, France;3. Institut de Génomique Fonctionnelle, Universités de Montpellier, CNRS UMR 5203, Montpellier, France;4. INSERM U661, Montpellier, France;5. CNRS UPR 9023, Montpellier Cedex 5, France;6. Hertie Institute for Clinical Brain Research, Tübingen, Germany;7. CHU Clermont-Ferrand, Service de pharmacologie, Clermont-Ferrand, France |
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Abstract: | 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-HT2A receptors, which are known to mediate SSRI-induced analgesia. 5-HT2A 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-HT2A receptor C-terminus, which disrupts 5-HT2A receptor–PDZ protein interactions, induced an antihyperalgesic effect in diabetic rats, which results from activation of 5-HT2A 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-HT2A receptor-operated Ca2+ responses in neurons, an effect mimicked by knockdown of PSD-95. Hence, 5-HT2A 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. |
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