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Blockade of glutamate mGlu5 receptors in a rat model of neuropathic pain prevents early over-expression of pro-apoptotic genes and morphological changes in dorsal horn lamina II.

Abstract：

:We used rats with a sciatic nerve chronic constrictive injury (CCI) and combined behavioural, molecular and morphological approaches to assess the involvement of mGlu5 receptors in neuropathic pain-associated hyperalgesia and spinal cord neuron apoptosis. Mechanical and thermal hyperalgesia developed 2-3 days after surgery. Morphological changes in the ipsilateral L4-L5 lamina II consisted of: (i) cell loss (38 +/- 5%), (ii) increased TUNEL-positive profiles, (iii) decreased SP-immunoreactive primary afferents, and (iv) reactive gliosis. Molecular expression data suggested a bi-phasic response of bcl-2 family genes in CCI. An early (2-3 days post-CCI) E2F1- and p53-independent apoptosis appeared in the spinal cord as the pro-apoptotic bax gene increased (320 +/- 19%), followed by an increased expression of the anti-apoptotic bcl-2 and bcl-xL genes (60 +/- 11% and 110 +/- 15%, respectively) 7 days from CCI. The selective mGlu5 receptor antagonist, MPEP (2 mg/kg i.p. twice daily), prevented the development of thermal hyperalgesia and transiently reduced mechanical hyperalgesia. Despite the MPEP treatment, which normalised bax/bcl-2 and bcl-xL/bcl-xS ratios at all times post-CCI, mechanical hyperalgesia reappeared by 7 days after CCI. Similarly, MPEP was cytoprotective at 3, but not 7 days post-CCI. This study shows that: (a) spinal cord neuron loss may be triggered by a p53- and E2F1-independent apoptosis in lamina II with the participation of glutamate mGlu5 receptors, (b) these receptors seem to be involved transiently, as their blockade was no longer protective by 7 days CCI, and (c) this delayed cell death occurred in the absence of Bax activation, suggesting the involvement of an alternative death pathway.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

de Novellis V,Siniscalco D,Galderisi U,Fuccio C,Nolano M,Santoro L,Cascino A,Roth KA,Rossi F,Maione S

doi

10.1016/j.neuropharm.2003.10.014

subject

Has Abstract

pub_date

2004-03-01 00:00:00

pages

468-79

issue

eissn

0028-3908

issn

1873-7064

pii

S0028390803004131

journal_volume

pub_type

杂志文章

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Blockade of glutamate mGlu5 receptors in a rat model of neuropathic pain prevents early over-expression of pro-apoptotic genes and morphological changes in dorsal horn lamina II.