Evaluation of Leukemia Inhibitory Factor (LIF) in a Rat Model of Postoperative Pain


      Postoperative pain remains a significant problem despite optimal treatment with current pharmaceutical agents. In an effort to provide better postoperative pain control, there is a need to understand the factors that contribute to the development of pain after surgery. Leukemia inhibitory factor (LIF) is a pleiotropic cytokine released from tissues after injury. We hypothesized that LIF expression in skin, muscle, and dorsal root ganglion (DRG) would increase after plantar incision. The mRNA and protein expression of LIF and LIF receptor (LIF-R) were measured after plantar incision in the rat. Pain behaviors, immunohistochemistry, and C-fiber heat responses to LIF were also studied. LIF expression increased after incision in skin and muscle, and LIF-R was present in large and small DRG neurons. LIF administration to the hindpaw increased pain behaviors, a process that was reversed by anti-LIF. However, LIF and anti-LIF treatment at the time of incision did not augment or ameliorate pain behaviors. LIF treatment activated the second messenger system, JAK-STAT3, in cultured DRG neurons, but failed to alter spontaneous activity or heat responses in C-fiber nociceptors. In conclusion, LIF is not a target for postoperative analgesia; LIF may be important for skin and muscle repair and regeneration after incision.


      This article highlights an incision pain model for the study of factors involved in nociception. The study demonstrates that LIF in is an unlikely target for novel early postoperative analgesics.

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        • Apfelbaum J.L.
        • Chen C.
        • Mehta S.S.
        • Gan T.J.
        Postoperative pain experience: Results from a national survey suggest postoperative pain continues to be undermanaged.
        Anesth Analg. 2003; 97: 534-540
        • Banik R.K.
        • Subieta A.R.
        • Wu C.
        • Brennan T.J.
        Increased nerve growth factor after rat plantar incision contributes to guarding behavior and heat hyperalgesia.
        Pain. 2005; 117: 68-76
        • Banner L.R.
        • Moayeri N.N.
        • Patterson P.H.
        Leukemia inhibitory factor is expressed in astrocytes following cortical brain injury.
        Exp Neurol. 1997; 147: 1-9
        • Banner L.R.
        • Patterson P.H.
        Major changes in the expression of the mrnas for cholinergic differentiation factor/leukemia inhibitory factor and its receptor after injury to adult peripheral nerves and ganglia.
        Proc Natl Acad Sci U S A. 1994; 91: 7109-7113
        • Banner L.R.
        • Patterson P.H.
        • Allchorne A.
        • Poole S.
        • Woolf C.J.
        Leukemia inhibitory factor is an anti-inflammatory and analgesic cytokine.
        J Neurosci. 1998; 18: 5456-5462
        • Bennett T.M.
        • Dowsing B.J.
        • Austin L.
        • Messina A.
        • Nicola N.A.
        • Morrison W.A.
        Anterograde transport of leukemia inhibitory factor within transected sciatic nerves.
        Muscle Nerve. 1999; 22: 78-87
        • Blanchard F.
        • Duplomb L.
        • Wang Y.
        • Robledo O.
        • Kinzie E.
        • Pitard V.
        • Godard A.
        • Jacques Y.
        • Baumann H.
        Stimulation of leukemia inhibitory factor receptor degradation by extracellular signal-regulated kinase.
        J Bio Chem. 2000; 275: 28793-28801
        • Brennan T.J.
        • Vandermeulen E.P.
        • Gebhart G.F.
        Characterization of a rat model of incisional pain.
        Pain. 1996; 64: 493-501
        • Cafferty W.B.
        • Gardiner N.J.
        • Gavazzi I.
        • Powell J.
        • McMahon S.B.
        • Heath J.K.
        • Munson J.
        • Cohen J.
        • Thompson S.W.
        Leukemia inhibitory factor determines the growth status of injured adult sensory neurons.
        J Neurosci. 2001; 21: 7161-7170
        • Corness J.
        • Shi T.J.
        • Xu Z.Q.
        • Brulet P.
        • Hökfelt T.
        Influence of leukemia inhibitory factor on galanin/GMAP and neuropeptide Y expression in mouse primary sensory neurons after axotomy.
        Exp Brain Res. 1996; 112: 79-88
        • Corness J.
        • Stevens B.
        • Fields R.D.
        • Hökfelt T.
        NGF and LIF both regulate galanin gene expression in primary DRG cultures.
        Neuroreport. 1998; 9: 1533-1536
        • Curtis R.
        • Scherer S.S.
        • Somogyi R.
        • Adryan K.M.
        • Ip N.Y.
        • Zhu Y.
        • Lindsay R.M.
        • DiStefano P.S.
        Retrograde axonal transport of LIF is increased by peripheral nerve injury: Correlation with increased LIF expression in distal nerve.
        Neuron. 1994; 12: 191-204
        • Gadient R.A.
        • Patterson P.H.
        Leukemia inhibitory factor, Interleukin 6, and other cytokines using the GP130 transducing receptor: Roles in inflammation and injury.
        Stem Cells. 1999; 17: 127-137
        • Gardiner N.J.
        • Cafferty W.B.
        • Slack S.E.
        • Thompson S.W.
        Expression of gp130 and leukaemia inhibitory factor receptor subunits in adult rat sensory neurones: Regulation by nerve injury.
        J Neurochem. 2002; 83: 100-109
        • Gyotoku E.
        • Morita E.
        • Kameyoshi Y.
        • Hiragun T.
        • Yamamoto S.
        • Hide M.
        The IL-6 family cytokines, interleukin-6, interleukin-11, oncostatin M, and leukemia inhibitory factor, enhance mast cell growth through fibroblast-dependent pathway in mice.
        Arch Dermatol Res. 2001; 293: 508-514
        • Hill C.E.
        • Harrison B.J.
        • Rau K.K.
        • Hougland M.T.
        • Bunge M.B.
        • Mendell L.M.
        • Petruska J.C.
        Skin incision induces expression of axonal regeneration-related genes in adult rat spinal sensory neurons.
        J Pain. 2010; 11: 1066-1073
        • Honore P.
        • Wade C.L.
        • Zhong C.
        • Harris R.R.
        • Wu C.
        • Ghayur T.
        • Iwakura Y.
        • Decker M.W.
        • Faltynek C.
        • Sullivan J.
        • Jarvis M.F.
        Interleukin-1alphabeta gene-deficient mice show reduced nociceptive sensitivity in models of inflammatory and neuropathic pain but not post-operative pain.
        BehavBrain Res. 2006; 167: 355-364
        • Hulse R.E.
        • Kunkler P.E.
        • Fedynyshyn J.P.
        • Kraig R.P.
        Optimization of multiplexed bead-based cytokine immunoassays for rat serum and brain tissue.
        J Neurosci Methods. 2004; 136: 87-98
        • Ito Y.
        • Yamamoto M.
        • Li M.
        • Doyu M.
        • Tanaka F.
        • Mutch T.
        • Mitsuma T.
        • Sobue G.
        Differential temporal expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTRF alpha, LIFR beta, IL-6R alpha and gp130) in injured peripheral nerves.
        Brain Res. 1998; 793: 321-327
        • Jarvis M.F.
        • Honore P.
        • Shieh C.C.
        • Chapman M.
        • Joshi S.
        • Zhang X.F.
        • Kort M.
        • Carroll W.
        • Marron B.
        • Atkinson R.
        • Thomas J.
        • Liu D.
        • Krambis M.
        • Liu Y.
        • McGaraughty S.
        • Chu K.
        • Roeloffs R.
        • Zhong C.
        • Mikusa J.P.
        • Hernandez G.
        • Gauvin D.
        • Wade C.
        • Zhu C.
        • Pai M.
        • Scanio M.
        • Shi L.
        • Drizin I.
        • Gregg R.
        • Matulenko M.
        • Hakeem A.
        • Gross M.
        • Johnson M.
        • Marsh K.
        • Wagoner P.K.
        • Sullivan J.P.
        • Faltynek C.R.
        • Krafte D.S.
        A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.
        Proc Natl Acad Sci. 2007; 104: 8520-8525
        • Kami K.
        • Morikawa Y.
        • Kawai Y.
        • Senba E.
        Leukemia inhibitory factor, glial cell line-derived neurotrophic factor, and their receptor expressions following muscle crush injury.
        Muscle Nerve. 1999; 22: 1576-1586
        • Kami K.
        • Morikawa Y.
        • Sekimoto M.
        • Senba E.
        Gene expression of receptors for IL-6, LIF, and CNTF in regenerating skeletal muscles.
        J Histochem Cytochem. 2000; 48: 1203-1214
        • Kurek J.B.
        • Austin L.
        • Cheema S.S.
        • Bartlett P.F.
        • Murphy M.
        Up-regulation of leukaemia inhibitory factor and interleukin-6 in transected sciatic nerve and muscle following denervation.
        NeuromusculDisord. 1996; 6: 105-114
        • Kurek J.B.
        • Bennett T.M.
        • Bower J.J.
        • Muldoon C.M.
        • Austin L.
        Leukaemia inhibitory factor (LIF) production in a mouse model of spinal trauma.
        Neurosci Lett. 1998; 249: 1-4
        • Lemke R.
        • Gadient R.A.
        • Patterson P.H.
        • Bigl V.
        • Schliebs R.
        Leukemia inhibitory factor (LIF) mRNA-expressing neuronal subpopulations in adult rat basal forebrain.
        Neurosci Lett. 1997; 229: 69-71
        • Livak K.J.
        • Schmittgen T.D.
        Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
        Methods. 2001; 25: 402-408
        • Lotz M.
        • Moats T.
        • Villiger P.
        Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis.
        J Clin Invest. 1992; 90: 888-896
        • Malin S.A.
        • Molliver D.C.
        • Koerber H.R.
        • Cornuet P.
        • Frye R.
        • Albers K.M.
        • Davis B.M.
        Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo.
        J Neurosci. 2006; 26: 8588-8599
        • Okamoto H.
        • Yamamura M.
        • Morita Y.
        • Harada S.
        • Makino H.
        • Ota Z.
        The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis.
        Arthritis Rhem. 1997; 40: 1096-1105
        • Patterson P.H.
        Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology.
        Proc Natl Acad Sci U S A. 1994; 91: 7833-7835
        • Reeh P.W.
        Sensory receptors in mammalian skin in an in vitro preparation.
        Neurosci Lett. 1986; 66: 141-166
        • Soilu-Hänninen M.
        • Broberg E.
        • Röyttä M.
        • Mattila P.
        • Rinne J.
        • Hukkanen V.
        Expression of LIF and LIF receptor beta in Alzheimer’s and Parkinson’s diseases.
        Acta Neurol Scand. 2010; 121: 44-50
        • Sugiura S.
        • Lahav R.
        • Han J.
        • Kou S.Y.
        • Banner L.R.
        • de Pablo F.
        • Patterson P.H.
        Leukaemia inhibitory factor is required for normal inflammatory responses to injury in the peripheral and central nervous systems in vivo and is chemotactic for macrophages in vitro.
        Eur J Neurosci. 2000; 12: 457-466
        • Szepietowski J.C.
        • Reich A.
        • McKenzie R.C.
        The multifunctional role of leukaemia inhibitory factor in cutaneous biology.
        Acta Dermatovenerol Alp Panonica Adriat. 2004; 13: 124-129
        • Szepietowski J.C.
        • Mckenzif T.C.
        • Keohane S.G.
        • Walder C.
        • Aldridge R.D.
        • Hunter J.A.
        Leukaemia inhibitory factor: Induction in the early phase of allergic contact dermatitis.
        Contact Dermatitis. 1997; 36: 21-25
        • Tang W.W.
        • Qi M.
        • Van G.Y.
        • Wariner G.P.
        • Samal B.
        Leukemia inhibitory factor ameliorates experimental anti-GBM Ab glomerulonephritis.
        Kidney Int. 1996; 50: 1922-1927
        • Thompson S.W.
        • Dray A.
        • Urban L.
        Leukemia inhibitory factor induces mechanical allodynia but not thermal hyperalgesia in the juvenile rat.
        Neuroscience. 1996; 71: 1091-1094
        • Ulich T.R.
        • Fann M.J.
        • Patterson P.H.
        • Williams J.H.
        • Samal B.
        • Del Castillo J.
        • Yin S.
        • Guo K.
        • Remick D.G.
        Intratracheal injection of LPS and cytokines. V. LPS induces expression of LIF and LIF inhibits acute inflammation.
        Am J Physiol. 1994; 267: L442-446
        • Waring P.M.
        • Waring L.J.
        • Billington T.
        • Metcalf D.
        Leukemia inhibitory factor protects against experimental lethal Escherichia coli septic shock in mice.
        Proc Natl Acad Sci U S A. 1995; 92: 1337-1341
        • Werner S.
        • Grose R.
        Regulation of wound healing by growth factors and cytokines.
        Physiol Rev. 2003; 83: 835-870
        • Wu C.
        • Boustany L.
        • Liang H.
        • Brennan T.J.
        Nerve growth factor expression after plantar incision in the rat.
        Anesthesiology. 2007; 107: 128-135
        • Wu C.
        • Erickson M.A.
        • Xu J.
        • Wild K.D.
        • Brennan T.J.
        Expression profile of nerve growth factor after muscle incision in the rat.
        Anesthesiology. 2009; 110: 140-149
        • Yamamori T.
        Localization of cholinergic differentiation factor/leukemia inhibitory factor mRNA in the rat brain and peripheral tissues.
        Proc Natl Acad Sci U S A. 1991; 88: 7298-7302
        • Zahn P.K.
        • Subieta A.
        • Park S.S.
        • Brennan T.J.
        Effect of blockade of nerve growth factor and tumor necrosis factor on pain behaviors after plantar incision.
        J Pain. 2004; 5: 157-163
        • Zimmermann M.
        Ethical guidelines for investigations of experimental pain in conscious animals.
        Pain. 1983; 16: 109-110