title: Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats.
abstract: Pro-inflammatory cytokine production after nociceptive stimuli is pivotal for hyperalgesia. As macrophage migration inhibitory factor (MIF), a pleiotropic cytokine produced mainly by nonneuronal tissue, has been involved in the regulation of neuronal functions, herein we examined the role for MIF in formalin-induced inflammatory pain model. MIF critically contributed to nociceptive behaviors following formalin injection. Specifically, spinal administration of a MIF inhibitor (ISO-1) prevented and reversed flinching responses in rats. Further examination showed that levels of both MIF and the MIF receptor CD74 were substantially increased within the ipsilateral spinal cord dorsal horn after formalin administration. Mechanistic studies revealed that MIF upregulated the expression of the spinal NMDA receptor subunit NR2B via the MAPK signaling pathway. Moreover, microglial cells were found to be the major source of spinal MIF after formalin administration by fluorescence colocalization. These data highlight spinal MIF plays a critical role in the pathogenesis of formalin-induced inflammatory pain and suggest MIF may be a potential target for therapy of such pathological condition.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, No. 22, Hankou Road, Nanjing 210093, Jiangsu, China Department of Anesthesiology, The Affiliated Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing 210004, Jiangsu, China The Institute of Pediatrics, The Affiliated Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing 210004, Jiangsu, China.
authors.forename: FuZhou
authors.initials: F
authors.lastname: Wang
authors.forename: XiaoFeng
authors.initials: X
authors.lastname: Shen
authors.forename: XiRong
authors.initials: X
authors.lastname: Guo
authors.forename: YuZhu
authors.initials: Y
authors.lastname: Peng
authors.forename: YuSheng
authors.initials: Y
authors.lastname: Liu
authors.forename: ShiQin
authors.initials: S
authors.lastname: Xu
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005557:Formaldehyde; D007839:Functional Laterality / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D007278:Injections, Spinal / Q000379:methods; D019746:Intramolecular Oxidoreductases / Q000097:blood* / Q000134:cerebrospinal fluid*; D007555:Isoxazoles / Q000494:pharmacology; D037102:Lectins / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood* / Q000134:cerebrospinal fluid*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D051928:CD47 Antigen; D005904:Glial Fibrillary Acidic Protein; D007555:Isoxazoles; D037102:Lectins; D008263:Macrophage Migration-Inhibitory Factors; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; D005557:Formaldehyde; D020929:Mitogen-Activated Protein Kinase Kinases; D019746:Intramolecular Oxidoreductases; C515599:Mif protein, rat