Microglial activation mediates de novo lysophosphatidic acid production in a model of neuropathic pain.
We recently demonstrated that de novo lysophosphatidic acid (LPA) production in the spinal cord occurs in the early phase after nerve injury or LPA injection, and underlies the peripheral mechanisms of neuropathic pain. In this study, we examined the possible involvement of spinal cord microglia in such LPA-mediated functions. Intrathecal LPA injection rapidly increased the gene expression of CD11b and protein expression of phosphor-p38, accompanied by a morphological change of microglia from a ramified to amoeboid shape. Although early treatment with minocycline significantly inhibited LPA-induced neuropathic pain-like behavior and microglial activation, late treatment did not. Early treatment with minocycline also blocked LPA-evoked de novo LPA production and the increased activation of cytosolic phospholipase A(2), an LPA synthesis-related enzyme. Similar results were observed when the sciatic nerve was partially injured: early, but not late, treatment with minocycline significantly inhibited the injury-induced neuropathic pain, microglial activation, de novo LPA production and the underlying increased activation of cytosolic phospholipase A(2) as well as calcium-independent phospholipase A(2), another LPA synthesis-related enzyme. These findings suggest that the early phase of microglial activation is involved in de novo LPA production, and that this underlies the initial mechanisms of nerve injury-induced neuropathic pain.
Ma
Lin
L
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Bunkyo-machi, Nagasaki, Japan.
Nagai
Jun
J
Ueda
Hiroshi
H
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015153:Blotting, Western; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008246:Lysophospholipids / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D008911:Minocycline / Q000494:pharmacology; D010146:Pain / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D039481:CD11b Antigen; D008246:Lysophospholipids; D048051:p38 Mitogen-Activated Protein Kinases; D054467:Phospholipases A2; D008911:Minocycline; C032881:lysophosphatidic acid