Spinal D-Serine Increases PKC-Dependent GluN1 Phosphorylation Contributing to the Sigma-1 Receptor-Induced Development of Mechanical Allodynia in a Mouse Model of Neuropathic Pain - 18/04/17
Abstract |
We have recently shown that spinal sigma-1 receptor (Sig-1R) activation facilitates nociception via an increase in phosphorylation of the N-methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). The present study was designed to examine whether the Sig-1R-induced facilitative effect on NMDA-induced nociception is mediated by D-serine, and whether D-serine modulates spinal pGluN1 expression and the development of neuropathic pain after chronic constriction injury (CCI) of the sciatic nerve. Intrathecal administration of the D-serine degrading enzyme, D-amino acid oxidase attenuated the facilitation of NMDA-induced nociception induced by the Sig-1R agonist, 2-(4-morpholinethyl)1-phenylcyclohexane carboxylate. Exogenous D-serine increased protein kinase C (PKC)-dependent (Ser896) pGluN1 expression and facilitated NMDA-induced nociception, which was attenuated by preteatment with the PKC inhibitor, chelerythrine. In CCI mice, administration of the serine racemase inhibitor, L-serine O-sulfate potassium salt or D-amino acid oxidase on postoperative days 0 to 3 suppressed CCI-induced mechanical allodynia (MA) and pGluN1 expression on day 3 after CCI surgery. Intrathecal administration of D-serine restored MA as well as the GluN1 phosphorylation on day 3 after surgery that was suppressed by the Sig-1R antagonist, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide or the astrocyte inhibitor, fluorocitrate. In contrast, D-serine had no effect on CCI-induced thermal hyperalgesia or GluN1 expression. These results indicate that spinal D-serine: 1) mediates the facilitative effect of Sig-1R on NMDA-induced nociception, 2) modulates PKC-dependent pGluN1 expression, and 3) ultimately contributes to the induction of MA after peripheral nerve injury.
Perspective |
This report shows that reducing D-serine suppresses central sensitization and significantly alleviates peripheral nerve injury-induced chronic neuropathic pain and that this process is modulated by spinal Sig-1Rs. This preclinical evidence provides a strong rationale for using D-serine antagonists to treat peripheral nerve injury-induced neuropathy.
Le texte complet de cet article est disponible en PDF.Highlights |
• | Spinal N-methyl-D-aspartate receptors play a key role in the development of central sensitization. |
• | D-serine modulated spinal protein kinase C-dependent (Ser896) phosphorylation of GluN1 subunit. |
• | D-serine mediated the effects of spinal sigma-1 receptors on phosphorylated GluN1 and nociception. |
• | D-serine contributed to the development of mechanical allodynia after peripheral nerve injury. |
Key words : D-serine, sigma-1 receptor, GluN1 phosphorylation, protein kinase C, neuropathic pain
Plan
| S.-R.C. and J.-Y.M. contributed equally to this work. |
|
| This work was supported by the National Research Foundation of Korea grant funded by the Korean Government (grant 2014R1A2A2A01007695). |
|
| The authors have no conflicts of interest to declare. |
Vol 18 - N° 4
P. 415-427 - avril 2017 Retour au numéro
Article précédent
- A Trial-Based Economic Evaluation Comparing Spinal Cord Stimulation With Best Medical Treatment in Painful Diabetic Peripheral Neuropathy
- Rachel Slangen, Catharina G. Faber, Nicolaas C. Schaper, Elbert A. Joosten, Robert T. van Dongen, Alfons G. Kessels, Maarten van Kleef, Carmen D. Dirksen
- Causal Mediation in the Development of Painful Temporomandibular Disorder
- Anne E. Sanders, Aderonke A. Akinkugbe, Roger B. Fillingim, Richard Ohrbach, Joel D. Greenspan, William Maixner, Eric Bair, Gary D. Slade
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?