Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats

FuZhou Wang; XiaoFeng Shen; XiRong Guo; YuZhu Peng; YuSheng Liu; ShiQin Xu; Jie Yang

doi:10.1016/j.pain.2009.11.011

Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats

Pain. 2010 Feb;148(2):275-283. doi: 10.1016/j.pain.2009.11.011. Epub 2009 Dec 11.

Authors

FuZhou Wang¹, XiaoFeng Shen, XiRong Guo, YuZhu Peng, YuSheng Liu, ShiQin Xu, Jie Yang

Affiliation

¹ 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.

PMID: 20005040
DOI: 10.1016/j.pain.2009.11.011

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analysis of Variance
Animals
CD47 Antigen / metabolism
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme-Linked Immunosorbent Assay / methods
Formaldehyde
Functional Laterality / physiology
Glial Fibrillary Acidic Protein / metabolism
Hyperalgesia / drug therapy
Hyperalgesia / etiology*
Hyperalgesia / pathology*
Inflammation / chemically induced
Inflammation / complications*
Injections, Spinal / methods
Intramolecular Oxidoreductases / blood*
Intramolecular Oxidoreductases / cerebrospinal fluid*
Isoxazoles / pharmacology
Lectins / metabolism
Macrophage Migration-Inhibitory Factors / blood*
Macrophage Migration-Inhibitory Factors / cerebrospinal fluid*
Male
Microglia / drug effects
Microglia / metabolism
Mitogen-Activated Protein Kinase Kinases / metabolism
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate / metabolism
Signal Transduction / drug effects
Spinal Cord / drug effects
Spinal Cord / metabolism*
Up-Regulation / drug effects
tau Proteins / metabolism

Substances

3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester
CD47 Antigen
Glial Fibrillary Acidic Protein
Isoxazoles
Lectins
Macrophage Migration-Inhibitory Factors
NR2B NMDA receptor
Receptors, N-Methyl-D-Aspartate
tau Proteins
Formaldehyde
Mitogen-Activated Protein Kinase Kinases
Intramolecular Oxidoreductases
Mif protein, rat