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

Mol Ther. 2010 Aug;18(8):1462-70. doi: 10.1038/mt.2010.101. Epub 2010 Jun 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

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