Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain.
Lysophosphatidic acid receptor (LPA(1)) 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 injection of LPA evoked a dose- and time-dependent down-regulation of myelin-associated glycoprotein (MAG) in the DR through LPA(1) 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 LPA(1) 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.
Xie
Weijiao
W
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Uchida
Hitoshi
H
Nagai
Jun
J
Ueda
Mutsumi
M
Chun
Jerold
J
Ueda
Hiroshi
H
D000818:Animals; D002154:Calpain / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008246:Lysophospholipids / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D010523:Peripheral Nervous System Diseases / Q000378:metabolism* / Q000503:physiopathology; D049368:Receptors, Lysophosphatidic Acid / Q000187:drug effects / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000378:metabolism / Q000503:physiopathology; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000473:pathology; D013126:Spinal Nerve Roots / Q000378:metabolism* / Q000473:pathology
D015853:Cysteine Proteinase Inhibitors; D008246:Lysophospholipids; D018992:Myelin-Associated Glycoprotein; D009498:Neurotoxins; D049368:Receptors, Lysophosphatidic Acid; D002154:Calpain; D007930:Leucine; C032881:lysophosphatidic acid; C024974:E 64