TY - JOUR
T1 - Simultaneous stimulation of spinal NK1 and NMDA receptors produces LPC which undergoes ATX-mediated conversion to LPA, an initiator of neuropathic pain
AU - Inoue, Makoto
AU - Ma, Lin
AU - Aoki, Junken
AU - Ueda, Hiroshi
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2008/12
Y1 - 2008/12
N2 - We previously reported that nerve injury-induced neuropathic pain and its underlying mechanisms are initiated by lysophosphatidic acid. In the present study, by measuring cell-rounding in a biological assay using lysophosphatidic acid 1 receptor-expressing B103 cells, we evaluated the molecular mechanism underlying lysophosphatidic acid biosynthesis following intense stimulation of primary afferents. Lysophosphatidic acid production was induced by treatment of spinal cord slices with capsaicin (10 μM), an intense stimulator of primary afferents, in the presence of recombinant autotaxin, but not in its absence. Lysophosphatidic acid was also induced by combination treatment of slices with high doses (10 and 30 μM) of substance P and NMDA, but not by other combinations of substance P, NMDA, calcitonin gene-related peptide and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (30 μM each) in the presence of recombinant autotaxin. We also found that following neurokinin 1 and NMDA receptor activation, activation of both cytosolic phospholipase A 2 and calcium-independent intracellular phospholipase A2 signalling pathways through protein kinase C and mitogen-activated protein/extracellular signal-regulated kinase activation and intracellular calcium elevation were required for lysophosphatidic acid production. These findings suggest that simultaneous intense stimulation of neurokinin 1 and NMDA receptors in the spinal dorsal horn triggers lysophosphatidic acid production from lysophosphatidylcholine through extracellular autotaxin.
AB - We previously reported that nerve injury-induced neuropathic pain and its underlying mechanisms are initiated by lysophosphatidic acid. In the present study, by measuring cell-rounding in a biological assay using lysophosphatidic acid 1 receptor-expressing B103 cells, we evaluated the molecular mechanism underlying lysophosphatidic acid biosynthesis following intense stimulation of primary afferents. Lysophosphatidic acid production was induced by treatment of spinal cord slices with capsaicin (10 μM), an intense stimulator of primary afferents, in the presence of recombinant autotaxin, but not in its absence. Lysophosphatidic acid was also induced by combination treatment of slices with high doses (10 and 30 μM) of substance P and NMDA, but not by other combinations of substance P, NMDA, calcitonin gene-related peptide and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (30 μM each) in the presence of recombinant autotaxin. We also found that following neurokinin 1 and NMDA receptor activation, activation of both cytosolic phospholipase A 2 and calcium-independent intracellular phospholipase A2 signalling pathways through protein kinase C and mitogen-activated protein/extracellular signal-regulated kinase activation and intracellular calcium elevation were required for lysophosphatidic acid production. These findings suggest that simultaneous intense stimulation of neurokinin 1 and NMDA receptors in the spinal dorsal horn triggers lysophosphatidic acid production from lysophosphatidylcholine through extracellular autotaxin.
KW - Autotaxin
KW - Capsaicin
KW - Lysophosphatidic acid
KW - Lysophosphatidylcholine
KW - Neuropathic pain
KW - Spinal cord
UR - http://www.scopus.com/inward/record.url?scp=56749154708&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=56749154708&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2008.05725.x
DO - 10.1111/j.1471-4159.2008.05725.x
M3 - Article
C2 - 19014389
AN - SCOPUS:56749154708
SN - 0022-3042
VL - 107
SP - 1556
EP - 1565
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 6
ER -