title: Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal cord contribute to the generation of neuropathic pain.
abstract: Leukotrienes (LTs) belong to a large family of lipid mediators, termed eicosanoids, which are derived from arachidonic acids and released from the cell membrane by phospholipases. LTs are involved in the pathogenesis of inflammatory diseases, such as asthma, rheumatoid arthritis, and peripheral inflammatory pain. In the present study, we examined whether LTs were implicated in pathomechanism of neuropathic pain following peripheral nerve injury. Using the spared nerve injury (SNI) model in rats, we investigated the expression of LT synthases (5-lipoxygenase; 5-LO, Five lipoxygenase activating protein; FLAP, LTA4 hydrolase; LTA4h and LTC4 synthase; LTC4s) and receptors (BLT1, 2 and CysLT1, 2) mRNAs in the rat spinal cord. Semi-quantitative RT-PCR revealed that 5-LO, FLAP, LTC4s, BLT1, and CysLT1 mRNAs increased following SNI, but not CysLT2 mRNAs. Using double labeling analysis of in situ hybridization with immunohistochemistry, we observed that 5-LO, FLAP, and CysLT1 mRNAs were expressed in spinal microglia. LTA4h and LTC4s mRNAs were expressed in both spinal neurons and microglia. BLT1 mRNA was expressed in spinal neurons. The p38 mitogen-activated protein kinase inhibitor, but not MEK inhibitor, reduced the increase in 5-LO in spinal microglia. Continuous intrathecal administration of the 5-LO inhibitor or BLT1 and CysLT1 receptor antagonists suppressed mechanical allodynia induced by SNI. Our findings suggest that the increase of LT synthesis in spinal microglia produced via p38 MAPK plays a role in the generation of neuropathic pain.
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Okubo
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016227:Benzoquinones / Q000627:therapeutic use; D002867:Chromones / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005233:Fatty Alcohols / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006018:Glycols / Q000627:therapeutic use; D006930:Hyperalgesia / Q000503:physiopathology; D020024:Leukotriene Antagonists / Q000627:therapeutic use; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000150:complications; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013997:Time Factors
chemical_list: D016227:Benzoquinones; D002867:Chromones; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D006018:Glycols; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; C062137:U 75302; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001094:Arachidonate 5-Lipoxygenase; D010751:Phosphopyruvate Hydratase; C083169:leukotriene D4 receptor; C047681:pranlukast