Increasing spinal 5-HT2A receptor responsiveness mediates anti-allodynic effect and potentiates fluoxetine efficacy in neuropathic rats. Evidence for GABA release.
Pharmacol Res
; 118: 93-103, 2017 04.
Article
em En
| MEDLINE
| ID: mdl-27663259
ABSTRACT
Antidepressants are one of the first line treatments for neuropathic pain but their use is limited by the incidence and severity of side effects of tricyclics and the weak effectiveness of selective serotonin reuptake inhibitors (SSRIs). Serotonin type 2A (5-HT2A) receptors interact with PDZ proteins that regulate their functionality and SSRI efficacy to alleviate pain. We investigated whether an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT2A receptors and associated PDZ proteins would improve the treatment of traumatic neuropathic allodynia. Tactile allodynia was assessed in spinal nerve ligation-induced neuropathic pain in rats using von Frey filaments after acute treatment with TAT-2ASCV and/or 5-HT2A receptor agonist, alone or in combination with repeated treatment with fluoxetine. In vivo microdialysis was performed in order to examine the involvement of GABA in TAT-2ASCV/fluoxetine treatment-associated analgesia. TAT-2ASCV (100ng, single i.t. injection) improved SNL-induced tactile allodynia by increasing 5-HT2A receptor responsiveness to endogenous 5-HT. Fluoxetine alone (10mg/kg, five i.p. injections) slightly increased tactile thresholds and its co-administration with TAT-2ASCV (100ng, single i.t. injection) further enhanced the anti-allodynic effect. This effect depends on the integrity of descending serotonergic bulbospinal pathways and spinal release of GABA. The anti-allodynic effect of fluoxetine can be enhanced by disrupting 5-HT2A receptor-PDZ protein interactions. This enhancement depends on 5-HT2A receptor activation, spinal GABA release and GABAA receptor activation.
Palavras-chave
5,7-Dihydroxytryptamine creatinin sulfate (PubChem CID: 35781); 5-HT(2A) receptors; Alpha-methyl-5-hydroxy-tryptamine maleate (PubChem CID: 2107); Bicuculline (PubChem CID: 10237); Desipramine (PubChem CID: 65327); Fluoxetine (PubChem CID: 62857); GABA; M100907 (PubChem CID:60858); Neuropathic pain; PDZ proteins; SSRIs; Tactile allodynia
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fluoxetina
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Receptor 5-HT2A de Serotonina
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Ácido gama-Aminobutírico
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Hiperalgesia
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Neuralgia
Limite:
Animals
Idioma:
En
Revista:
Pharmacol Res
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
França