Increasing spinal 5-HT2Areceptor responsiveness mediates anti-allodynic effect and potentiates fluoxetine efficacy in neuropathic rats. Evidence for GABA release.
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-HT2Areceptors 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-HT2Areceptor 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-HT2Areceptor 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-HT2Areceptor-PDZ protein interactions. This enhancement depends on 5-HT2Areceptor activation, spinal GABA release and GABAA receptor activation.
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France.
Amandine
A
Dupuis
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France.
Anne-Sophie
AS
Wattiez
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; CHU Clermont-Ferrand, Service de Pharmacologie, Clermont-Ferrand, France.
Jérémy
J
Pinguet
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; CHU Clermont-Ferrand, Service de Pharmacologie, Clermont-Ferrand, France.
Damien
D
Richard
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; CHU Clermont-Ferrand, Service de Pharmacologie, Clermont-Ferrand, France.
Frédéric
F
Libert
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France.
Maryse
M
Chalus
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France.
Youssef
Y
Aissouni
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France.
Benoit
B
Sion
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France.
Denis
D
Ardid
Institut de Génomique Fonctionnelle, CNRS, UMR 5203, INSERM U1191, Université de Montpellier, F-34094 Montpellier Cedex 5, France.
Philippe
P
Marin
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; CHU Clermont-Ferrand, Service de Pharmacologie, Clermont-Ferrand, France.
Alain
A
Eschalier
INSERM, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France. Electronic address: christine.courteix@udamail.fr.
Christine
C
Courteix
D000818:Animals; D004357:Drug Synergism; D005473:Fluoxetine / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology; D013116:Spinal Cord / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D044402:Receptor, Serotonin, 5-HT2A; D011963:Receptors, GABA-A; D005473:Fluoxetine; D005680:gamma-Aminobutyric Acid
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