title: Macrophage migration inhibitory factor (MIF) is essential for inflammatory and neuropathic pain and enhances pain in response to stress.
abstract: Stress and glucocorticoids exacerbate pain via undefined mechanisms. Macrophage migration inhibitory factor (MIF) is a constitutively expressed protein that is secreted to maintain immune function when glucocorticoids are elevated by trauma or stress. Here we show that MIF is essential for the development of neuropathic and inflammatory pain, and for stress-induced enhancement of neuropathic pain. Mif null mutant mice fail to develop pain-like behaviors in response to inflammatory stimuli or nerve injury. Pharmacological inhibition of MIF attenuates pain-like behaviors caused by nerve injury and prevents sensitization of these behaviors by stress. Conversely, injection of recombinant MIF into naïve mice produces dose-dependent mechanical sensitivity that is exacerbated by stress. MIF elicits pro-inflammatory signaling in microglia and activates sensory neurons, mechanisms that underlie pain. These data implicate MIF as a key regulator of pain and provide a mechanism whereby stressors exacerbate pain. MIF inhibitors warrant clinical investigation for the treatment of chronic pain.
authors.affiliation: Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Alexander
authors.forename: Gina M
authors.initials: GM
authors.lastname: Cox
authors.forename: Jin-Bin
authors.initials: JB
authors.lastname: Tian
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Zha
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Kigerl
authors.forename: Mahesh K
authors.initials: MK
authors.lastname: Reddy
authors.forename: Nilesh M
authors.initials: NM
authors.lastname: Dagia
authors.forename: Theis
authors.initials: T
authors.lastname: Sielecki
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.forename: Dana M
authors.initials: DM
authors.lastname: McTigue
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Whitacre
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010147:Pain Measurement / Q000379:methods; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse