Advertisement

Spatiotemporal Pattern of Concurrent Spinal and Supraspinal NF-κB Expression After Peripheral Nerve Injury

  • Chiu-Wen Chou
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Department of Anaesthesiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
    Search for articles by this author
  • Gordon T.C. Wong
    Affiliations
    Department of Anaesthesiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
    Search for articles by this author
  • Grewo Lim
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Shuxing Wang
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Michael G. Irwin
    Affiliations
    Department of Anaesthesiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
    Search for articles by this author
  • Jianren Mao
    Correspondence
    Address reprint requests to Dr Jianren Mao, MGH Center for Translational Pain Research, Department of Anesthesia and Critical Care, WACC 324, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author

      Abstract

      The expression of NF-κB in the spinal cord is associated with neuropathic pain. However, little is known about its expression beyond the spinal cord. Here we examined a spatial and temporal pattern of the NF-κB expression in both spinal and supraspinal regions. After chronic constriction injury (CCI) of the sciatic nerve, NF-κB (p65) expression was significantly increased in the ipsilateral spinal cord. In contrast, the NF-κB expression in the contralateral primary somatosensory cortex was decreased with no significant differences seen in the thalamus. In the contralateral anterior cingulate cortex, the NF-κB expression was increased significantly on day 14 as compared with the sham group. In the contralateral amygdala, the NF-κB expression showed a time-dependent downregulation after CCI, which became significant on day 14. MK-801 reduced nociceptive behaviors and reversed the direction of NF-κB expression. These results indicate that the CCI-induced expression of p65 NF-κB is both time-dependent and region-specific, in areas that process both sensory-discriminative and motivational-affective dimensions of pain.

      Perspective

      This article presents a spatiotemporal mapping of the NF-κB expression in spinal and supraspinal regions after peripheral nerve injury. These findings point to an involvement of NF-κB beyond the spinal cord in both the sensory discriminative and emotional affective aspects of neuropathic pain processing.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Boersma M.C.
        • Meffert M.K.
        Novel roles for the NF-kappaB signaling pathway in regulating neuronal function.
        Sci Signal. 2008; 1: pe7
        • Bruggemann J.
        • Galhardo V.
        • Apkarian A.V.
        Immediate reorganization of the rat somatosensory thalamus after partial ligation of sciatic nerve.
        J Pain. 2001; 2: 220-228
        • Bushnell M.C.
        • Duncan G.H.
        • Hofbauer R.K.
        • Ha B.
        • Chen J.I.
        • Carrier B.
        Pain perception: Is there a role for primary somatosensory cortex?.
        Proc Natl Acad Sci U S A. 1999; 96: 7705-7709
        • Chizh B.A.
        • Headley P.M.
        NMDA antagonists and neuropathic pain: Multiple drug targets and multiple uses.
        Curr Pharm Des. 2005; 11: 2977-2994
        • Costigan M.
        • Scholz J.
        • Woolf C.J.
        Neuropathic pain: A maladaptive response of the nervous system to damage.
        Annu Rev Neurosci. 2009; 32: 1-32
        • Endo T.
        • Spenger C.
        • Hao J.
        • Tominaga T.
        • Wiesenfeld-Hallin Z.
        • Olson L.
        • Xu X.J.
        Functional MRI of the brain detects neuropathic pain in experimental spinal cord injury.
        Pain. 2008; 138: 292-300
        • Flor H.
        • Elbert T.
        • Knecht S.
        • Wienbruch C.
        • Pantev C.
        • Birbaumer N.
        • Larbig W.
        • Taub E.
        Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation.
        Nature. 1995; 375: 482-484
        • Gybels J.
        Thalamic stimulation in neuropathic pain: 27 years later.
        Acta Neurol Belg. 2001; 101: 65-71
        • Hargreaves K.
        • Dubner R.
        • Brown F.
        • Flores C.
        • Joris J.
        A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.
        Pain. 1988; 32: 77-88
        • Jhaveri M.D.
        • Elmes S.J.
        • Richardson D.
        • Barrett D.A.
        • Kendall D.A.
        • Mason R.
        • Chapman V.
        Evidence for a novel functional role of cannabinoid CB(2) receptors in the thalamus of neuropathic rats.
        Eur J Neurosci. 2008; 27: 1722-1730
        • Ji R.R.
        • Kohno T.
        • Moore K.A.
        • Woolf C.J.
        Central sensitization and LTP: Do pain and memory share similar mechanisms?.
        Trends Neurosci. 2003; 26: 696-705
        • Kaltschmidt C.
        • Kaltschmidt B.
        • Neumann H.
        • Wekerle H.
        • Baeuerle P.A.
        Constitutive NF-kappa B activity in neurons.
        Mol Cell Biol. 1994; 14: 3981-3992
        • Ko S.W.
        • Vadakkan K.I.
        • Ao H.
        • Gallitano-Mendel A.
        • Wei F.
        • Milbrandt J.
        • Zhuo M.
        Selective contribution of Egr1 (zif/268) to persistent inflammatory pain.
        J Pain. 2005; 6: 12-20
        • Korner M.
        • Rattner A.
        • Mauxion F.
        • Sen R.
        • Citri Y.
        A brain-specific transcription activator.
        Neuron. 1989; 3: 563-572
        • Kuzumaki N.
        • Narita M.
        • Hareyama N.
        • Niikura K.
        • Nagumo Y.
        • Nozaki H.
        • Amano T.
        • Suzuki T.
        Chronic pain-induced astrocyte activation in the cingulate cortex with no change in neural or glial differentiation from neural stem cells in mice.
        Neurosci Lett. 2007; 415: 22-27
        • LaGraize S.C.
        • Fuchs P.N.
        GABAA but not GABAB receptors in the rostral anterior cingulate cortex selectively modulate pain-induced escape/avoidance behavior.
        Exp Neurol. 2007; 204: 182-194
        • LaGraize S.C.
        • Labuda C.J.
        • Rutledge M.A.
        • Jackson R.L.
        • Fuchs P.N.
        Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain.
        Exp Neurol. 2004; 188: 139-148
        • Laughlin T.M.
        • Bethea J.R.
        • Yezierski R.P.
        • Wilcox G.L.
        Cytokine involvement in dynorphin-induced allodynia.
        Pain. 2000; 84: 159-167
      1. Liou H.-C. NF-κB/Rel Transcription Factor Family. Springer, New York, NY2006
        • Ma W.
        • Bisby M.A.
        Increased activation of nuclear factor kappa B in rat lumbar dorsal root ganglion neurons following partial sciatic nerve injuries.
        Brain Res. 1998; 797: 243-254
        • Mao J.
        • Mayer D.J.
        • Price D.D.
        Patterns of increased brain activity indicative of pain in a rat model of peripheral mononeuropathy.
        J Neurosci. 1993; 13: 2689-2702
        • Mao J.
        • Price D.D.
        • Mayer D.J.
        • Lu J.
        • Hayes R.L.
        Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy.
        Brain Res. 1992; 576: 254-262
        • Mattson M.P.
        • Camandola S.
        NF-kappaB in neuronal plasticity and neurodegenerative disorders.
        J Clin Invest. 2001; 107: 247-254
        • Meffert M.K.
        • Chang J.M.
        • Wiltgen B.J.
        • Fanselow M.S.
        • Baltimore D.
        NF-kappa B functions in synaptic signaling and behavior.
        Nat Neurosci. 2003; 6: 1072-1078
        • Melzack R.
        • Casey K.L.
        Sensory, motivational, and central control determinants of pain.
        in: Kenshalo D. The Skin Senses. CC Thomas, Springfield1968: 423-439
        • Meunier A.
        • Latremoliere A.
        • Dominguez E.
        • Mauborgne A.
        • Philippe S.
        • Hamon M.
        • Mallet J.
        • Benoliel J.J.
        • Pohl M.
        Lentiviral-mediated targeted NF-kappaB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat.
        Mol Ther. 2007; 15: 687-697
        • Moynagh P.N.
        • Williams D.C.
        • O'Neill L.A.
        Interleukin-1 activates transcription factor NF kappa B in glial cells.
        Biochem J. 1993; 294: 343-347
        • Narita M.
        • Kuzumaki N.
        • Kaneko C.
        • Hareyama N.
        • Miyatake M.
        • Shindo K.
        • Miyoshi K.
        • Nakajima M.
        • Nagumo Y.
        • Sato F.
        • Wachi H.
        • Seyama Y.
        • Suzuki T.
        Chronic pain-induced emotional dysfunction is associated with astrogliosis due to cortical delta-opioid receptor dysfunction.
        J Neurochem. 2006; 97: 1369-1378
        • Narita M.
        • Ozaki S.
        • Ise Y.
        • Yajima Y.
        • Suzuki T.
        Change in the expression of c-fos in the rat brain following sciatic nerve ligation.
        Neurosci Lett. 2003; 352: 231-233
        • Navarro X.
        • Vivo M.
        • Valero-Cabre A.
        Neural plasticity after peripheral nerve injury and regeneration.
        Prog Neurobiol. 2007; 82: 163-201
        • Neugebauer V.
        • Galhardo V.
        • Maione S.
        • Mackey S.C.
        Forebrain pain mechanisms.
        Brain Res Rev. 2009; 60: 226-242
        • Neugebauer V.
        • Li W.
        • Bird G.C.
        • Han J.S.
        The amygdala and persistent pain.
        Neuroscientist. 2004; 10: 221-234
        • O'Neill L.A.
        • Kaltschmidt C.
        • NF-kappa B.
        A crucial transcription factor for glial and neuronal cell function.
        Trends Neurosci. 1997; 20: 252-258
        • O'Rielly D.D.
        • Loomis C.W.
        Spinal nerve ligation-induced activation of nuclear factor kappaB is facilitated by prostaglandins in the affected spinal cord and is a critical step in the development of mechanical allodynia.
        Neuroscience. 2008; 155: 902-913
        • Ohara P.T.
        • Vit J.P.
        • Jasmin L.
        Cortical modulation of pain.
        Cell Mol Life Sci. 2005; 62: 44-52
        • Owen S.L.
        • Green A.L.
        • Stein J.F.
        • Aziz T.Z.
        Deep brain stimulation for the alleviation of post-stroke neuropathic pain.
        Pain. 2006; 120: 202-206
      2. Paxinos G. Watson C. The Rat Brain in Stereotaxic Coordinates. 4th ed. Academic Press, San Diego, CA1998
        • Pedersen L.H.
        • Scheel-Kruger J.
        • Blackburn-Munro G.
        Amygdala GABA-A receptor involvement in mediating sensory-discriminative and affective-motivational pain responses in a rat model of peripheral nerve injury.
        Pain. 2007; 127: 17-26
        • Price D.D.
        • Sufka K.J.
        Theories of pain.
        in: Mao J. Translational Pain Research. Vol. I. Nova Science Publishers, New York2006: 1-27
        • Saade N.E.
        • Jabbur S.J.
        Nociceptive behavior in animal models for peripheral neuropathy: Spinal and supraspinal mechanisms.
        Prog Neurobiol. 2008; 86: 22-47
        • Sakaue G.
        • Shimaoka M.
        • Fukuoka T.
        • Hiroi T.
        • Inoue T.
        • Hashimoto N.
        • Sakaguchi T.
        • Sawa Y.
        • Morishita R.
        • Kiyono H.
        • Noguchi K.
        • Mashimo T.
        NF-kappa B decoy suppresses cytokine expression and thermal hyperalgesia in a rat neuropathic pain model.
        Neuroreport. 2001; 12: 2079-2084
        • Scholz J.
        • Broom D.C.
        • Youn D.H.
        • Mills C.D.
        • Kohno T.
        • Suter M.R.
        • Moore K.A.
        • Decosterd I.
        • Coggeshall R.E.
        • Woolf C.J.
        Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury.
        J Neurosci. 2005; 25: 7317-7323
        • Shyu B.C.
        • Vogt B.A.
        Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway.
        Mol Pain. 2009; 5: 51
        • Sparacio S.M.
        • Zhang Y.
        • Vilcek J.
        • Benveniste E.N.
        Cytokine regulation of interleukin-6 gene expression in astrocytes involves activation of an NF-kappa B-like nuclear protein.
        J Neuroimmunol. 1992; 39: 231-242
        • Takeda R.
        • Watanabe Y.
        • Ikeda T.
        • Abe H.
        • Ebihara K.
        • Matsuo H.
        • Nonaka H.
        • Hashiguchi H.
        • Nishimori T.
        • Ishida Y.
        Analgesic effect of milnacipran is associated with c-Fos expression in the anterior cingulate cortex in the rat neuropathic pain model.
        Neurosci Res. 2009; 64: 380-384
        • Tal M.
        • Bennett G.J.
        Extra-territorial pain in rats with a peripheral mononeuropathy: Mechano-hyperalgesia and mechano-allodynia in the territory of an uninjured nerve.
        Pain. 1994; 57: 375-382
        • Wei F.
        • Qiu C.S.
        • Kim S.J.
        • Muglia L.
        • Maas J.W.
        • Pineda V.V.
        • Xu H.M.
        • Chen Z.F.
        • Storm D.R.
        • Muglia L.J.
        • Zhuo M.
        Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases.
        Neuron. 2002; 36: 713-726
        • Wei F.
        • Wang G.D.
        • Kerchner G.A.
        • Kim S.J.
        • Xu H.M.
        • Chen Z.F.
        • Zhuo M.
        Genetic enhancement of inflammatory pain by forebrain NR2B overexpression.
        Nat Neurosci. 2001; 4: 164-169
        • Wrigley P.J.
        • Press S.R.
        • Gustin S.M.
        • Macefield V.G.
        • Gandevia S.C.
        • Cousins M.J.
        • Middleton J.W.
        • Henderson L.A.
        • Siddall P.J.
        Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury.
        Pain. 2009; 141: 52-59
        • Wu L.J.
        • Toyoda H.
        • Zhao M.G.
        • Lee Y.S.
        • Tang J.
        • Ko S.W.
        • Jia Y.H.
        • Shum F.W.
        • Zerbinatti C.V.
        • Bu G.
        • Wei F.
        • Xu T.L.
        • Muglia L.J.
        • Chen Z.F.
        • Auberson Y.P.
        • Kaang B.K.
        • Zhuo M.
        Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation.
        J Neurosci. 2005; 25: 11107-11116
        • Xie Y.F.
        • Huo F.Q.
        • Tang J.S.
        Cerebral cortex modulation of pain.
        Acta Pharmacol Sin. 2009; 30: 31-41
        • Xu H.
        • Wu L.J.
        • Wang H.
        • Zhang X.
        • Vadakkan K.I.
        • Kim S.S.
        • Steenland H.W.
        • Zhuo M.
        Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex.
        J Neurosci. 2008; 28: 7445-7453
        • Zhuo M.
        Molecular mechanisms of pain in the anterior cingulate cortex.
        J Neurosci Res. 2006; 84: 927-933