Calpain‐mediated down‐regulation of myelin‐associated glycoprotein in lysophosphatidic acid‐induced neuropathic pain

• Published in: Journal of neurochemistry Vol. 113; no. 4; pp. 1002 - 1011
• Main Authors: Xie, Weijiao, Uchida, Hitoshi, Nagai, Jun, Ueda, Mutsumi, Chun, Jerold, Ueda, Hiroshi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2010; Wiley-Blackwell
• Subjects: Acids; Analytical, structural and metabolic biochemistry; Animals; Biochemistry; Biological and medical sciences; calpain; Calpain - metabolism; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Cysteine Proteinase Inhibitors - pharmacology; Demyelinating Diseases - etiology; Demyelinating Diseases - metabolism; Demyelinating Diseases - physiopathology; demyelination; Disease Models, Animal; dorsal root; Enzyme Activation - drug effects; Enzyme Activation - physiology; Fundamental and applied biological sciences. Psychology; Glycoproteins; Leucine - analogs & derivatives; Leucine - pharmacology; lysophosphatidic acid; Lysophospholipids - toxicity; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin-Associated Glycoprotein - metabolism; myelin‐associated glycoprotein; Nervous system (semeiology, syndromes); Neurology; neuropathic pain; Neurotoxins - toxicity; Pain management; Peripheral Nervous System Diseases - metabolism; Peripheral Nervous System Diseases - physiopathology; Proteins; Receptors, Lysophosphatidic Acid - drug effects; Receptors, Lysophosphatidic Acid - metabolism; Sciatic Neuropathy - metabolism; Sciatic Neuropathy - physiopathology; Sensory Receptor Cells - metabolism; Sensory Receptor Cells - pathology; Signal transduction; Spinal Nerve Roots - metabolism; Spinal Nerve Roots - pathology; Nervous system diseases; Myelin; dorsal root; Activation; Inflammation; Myelin-associated glycoprotein; Protein; edg2 lysophospholipid receptor; Signal transduction; calpain; neuropathic pain; Pain; Treatment; Lysophosphatidic acid; demyelination; Models; Neuralgia; Neurological disorder; Sciatic nerve
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06664.x

J. Neurochem. (2010) 113, 1002–1011. 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 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.