Disrupting 5-HT(2A) receptor/PDZ protein interactions reduces hyperalgesia and enhances SSRI efficacy in neuropathic pain.

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-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.

• Authors: Xavier Pichon, Anne S Wattiez, Carine Becamel, Ingrid Ehrlich, Joel Bockaert, Alain Eschalier, Philippe Marin, Christine Courteix
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 18 Issue 8 Pg. 1462-70 (Aug 2010) ISSN: 1525-0024 [Electronic] United States
• PMID: 20531396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, Serotonin, 5-HT2A
• Serotonin Uptake Inhibitors
• Fluoxetine

Topics

• Animals
• Blotting, Western
• Chromatography, Affinity
• Diabetic Nephropathies (drug therapy, 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)
• Selective Serotonin Reuptake Inhibitors (therapeutic use)
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization