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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

Keywords : analogs & derivatives,Animals,Calpain,Cysteine Proteinase Inhibitors,Demyelinating Diseases,Disease Models,Animal,drug effects,Enzyme Activation,etiology,Freund’s Adjuvant,Hyperalgesia,Inflammation,injuries,Leucine,Lysophospholipids,Male,metabolism,Mice,Mice,Inbred C57BL,Mice,Knockout,Myelin-Associated Glycoprotein,Neurotoxins,Pain,pathology,Peripheral Nervous System Diseases,pharmacology,physiology,physiopathology,Receptors,Lysophosphatidic Acid,Sciatic Nerve,Sciatic Neuropathy,Sensory Receptor Cells,Spinal Nerve Roots,toxicity,, Downregulation,Myelinassociated,Glycoprotein, botox for pain in neck

Date of Publication : 2010 May

Authors : Xie W;Uchida H;Nagai J;Ueda M;Chun J;Ueda H;

Organisation : Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Journal of Publication : J Neurochem

Pubmed Link : https://www.ncbi.nlm.nih.gov/pubmed/20420580

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