title: Role of lipocalin-2-chemokine axis in the development of neuropathic pain following peripheral nerve injury.
abstract: Lipocalin 2 (LCN2), which is also known as 24p3 and neutrophil gelatinase-associated lipocalin (NGAL), binds small, hydrophobic ligands and interacts with cell surface receptor 24p3R to regulate diverse cellular processes. In the present study, we examined the role of LCN2 in the pathogenesis of neuropathic pain using a mouse model of spared nerve injury (SNI). Lcn2 mRNA levels were significantly increased in the dorsal horn of the spinal cord after SNI, and LCN2 protein was mainly localized in neurons of the dorsal and ventral horns. LCN2 receptor 24p3R was expressed in spinal neurons and microglia after SNI. Lcn2-deficient mice exhibited significantly less mechanical pain hypersensitivity during the early phase after SNI, and an intrathecal injection of recombinant LCN2 protein elicited mechanical pain hypersensitivity in naive animals. Lcn2 deficiency, however, did not affect acute nociceptive pain. Lcn2-deficient mice showed significantly less microglial activation and proalgesic chemokine (CCL2 and CXCL1) production in the spinal cord after SNI than wild-type mice, and recombinant LCN2 protein induced the expression of these chemokines in cultured neurons. Furthermore, the expression of LCN2 and its receptor was detected in neutrophils and macrophages in the sciatic nerve following SNI, suggesting the potential role of peripheral LCN2 in neuropathic pain. Taken together, our results indicate that LCN2 plays a critical role in the development of pain hypersensitivity following peripheral nerve injury and suggest that LCN2 mediates neuropathic pain by inducing chemokine expression and subsequent microglial activation.
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
authors.forename: Sangmin
authors.initials: S
authors.lastname: Jeon
authors.forename: Mithilesh Kumar
authors.initials: MK
authors.lastname: Jha
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Ock
authors.forename: Jungwan
authors.initials: J
authors.lastname: Seo
authors.forename: Myungwon
authors.initials: M
authors.lastname: Jin
authors.forename: Heejung
authors.initials: H
authors.lastname: Cho
authors.forename: Won-Ha
authors.initials: WH
authors.lastname: Lee
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008954:Models, Biological; D009437:Neuralgia / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059225:Nociception / Q000187:drug effects; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D059348:Peripheral Nerve Injuries / Q000150:complications* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D018925:Chemokines; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D048051:p38 Mitogen-Activated Protein Kinases; C508313:Slc22a17 protein, mouse; C071332:Lcn2 protein, mouse
keywords: Chemokines; Glia; Nerve; Neuroinflammation; Neuropathic Pain; Pain; Spinal Cord