Simultaneous stimulation of spinal NK1 and NMDA receptors produces LPC which undergoes ATX-mediated conversion to LPA, an initiator of neuropathic pain.
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 microM), 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 microM) of substance P and NMDA, but not by other combinations of substance P, NMDA, calcitonin gene-related peptide and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (30 microM 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 A(2) 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.
Inoue
Makoto
M
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Ma
Lin
L
Aoki
Junken
J
Ueda
Hiroshi
H
D000344:Afferent Pathways / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009097:Multienzyme Complexes / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D043264:Phosphodiesterase I / Q000134:cerebrospinal fluid / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D011493:Protein Kinase C / Q000378:metabolism; D011755:Pyrophosphatases / Q000134:cerebrospinal fluid / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D000099189:Lysophospholipase D
D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D018690:Excitatory Amino Acid Agonists; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D016202:N-Methylaspartate; D043264:Phosphodiesterase I; D054467:Phospholipases A2; D010727:Phosphoric Diester Hydrolases; D011493:Protein Kinase C; D011755:Pyrophosphatases; D049368:Receptors, Lysophosphatidic Acid; D016194:Receptors, N-Methyl-D-Aspartate; D018040:Receptors, Neurokinin-1; D013373:Substance P; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid