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.
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.
Key words
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Article Info
Publication History
Published online: December 13, 2016
Received in revised form:
October 22,
2016
Received:
August 1,
2016
Footnotes
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.
Identification
Copyright
© 2017 Published by Elsevier Inc. on behalf of the American Pain Society
