RGD Reference Report - Disrupting 5-HT(2A) receptor/PDZ protein interactions reduces hyperalgesia and enhances SSRI efficacy in neuropathic pain. - Rat Genome Database

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

Authors: Pichon, X  Wattiez, AS  Becamel, C  Ehrlich, I  Bockaert, J  Eschalier, A  Marin, P  Courteix, C 
Citation: Pichon X, etal., Mol Ther. 2010 Aug;18(8):1462-70. doi: 10.1038/mt.2010.101. Epub 2010 Jun 8.
RGD ID: 7257680
Pubmed: PMID:20531396   (View Abstract at PubMed)
PMCID: PMC2927054   (View Article at PubMed Central)
DOI: DOI:10.1038/mt.2010.101   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
DLG4HumanHyperalgesia  ISODlg4 (Rattus norvegicus)associated with Diabetic Neuropathies:RGD 
Dlg4RatHyperalgesia  IDA associated with Diabetic neuropathiesRGD 
Dlg4MouseHyperalgesia  ISODlg4 (Rattus norvegicus)associated with Diabetic Neuropathies:RGD 
HTR2AHumanHyperalgesia  ISOHtr2a (Rattus norvegicus)associated with Diabetic neuropathiesRGD 
Htr2aRatHyperalgesia  IDA associated with Diabetic neuropathiesRGD 
Htr2aMouseHyperalgesia  ISOHtr2a (Rattus norvegicus)associated with Diabetic neuropathiesRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Dlg4Ratprotein binding  IPIHtr2a (Rattus norvegicus) RGD 
Htr2aRatprotein binding  IPIDlg1 (Rattus norvegicus) and Dlg4 (Rattus norvegicus)associated with Diabetic Neuropathies:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dlg4  (discs large MAGUK scaffold protein 4)
Htr2a  (5-hydroxytryptamine receptor 2A)

Genes (Mus musculus)
Dlg4  (discs large MAGUK scaffold protein 4)
Htr2a  (5-hydroxytryptamine (serotonin) receptor 2A)

Genes (Homo sapiens)
DLG4  (discs large MAGUK scaffold protein 4)
HTR2A  (5-hydroxytryptamine receptor 2A)


Additional Information