These authors contributed equally to this study.
Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain
Article first published online: 2 MAR 2010
Journal Compilation © 2010 International Society for Neurochemistry
- Issue published online: 2 MAR 2010
- Article first published online: 2 MAR 2010
- Accepted manuscript online: 4 AUG 2010 12:14PM EST
- Received Date : 30-Nov-2009Revised Date : 20-Feb-2010Accepted Date : 22-Feb-2010
- lysophosphatidic acid;
- neuropathic pain;
- myelin-associated glycoprotein;
- dorsal root;
Lysophosphatidic acid receptor (LPA1) signaling initiates neuropathic pain through demyelination of the dorsal root (DR). Although LPA is found to cause down-regulation of myelin proteins underlying demyelination, the detailed mechanism remains to be determined. In the present study, we found that a single intrathecal (i.t.) injection of LPA evoked a dose- and time-dependent down-regulation of myelin-associated glycoprotein (MAG) in the DR through LPA1 receptor. A similar event was also observed in ex vivo DR cultures. Interestingly, LPA-induced down-regulation of MAG was significantly inhibited by calpain inhibitors (calpain inhibitor X, E-64 and E-64d) and LPA markedly induced calpain activation in the DR. The pre-treatment with calpain inhibitors attenuated LPA-induced neuropathic pain behaviors such as hyperalgesia and allodynia. Moreover, we found that sciatic nerve injury activates calpain activity in the DR in a LPA1 receptor-dependent manner. The E-64d treatments significantly blocked nerve injury-induced MAG down-regulation and neuropathic pain. However, there was no significant calpain activation in the DR by complete Freund’s adjuvant treatment, and E-64d failed to show anti-hyperalgesic effects in this inflammation model. The present study provides strong evidence that LPA-induced calpain activation plays a crucial role in the manifestation of neuropathic pain through MAG down-regulation in the DR.