Advertisement

Protein Kinase B/Akt Is Required for Complete Freund's Adjuvant-Induced Upregulation of Nav1.7 and Nav1.8 in Primary Sensory Neurons

  • Lingli Liang
    Affiliations
    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Longchang Fan
    Affiliations
    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

    Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
    Search for articles by this author
  • Bo Tao
    Affiliations
    Undergraduate Program in Public Health Studies, Johns Hopkins University Zanvyl Krieger School of Arts and Sciences, Baltimore, Maryland
    Search for articles by this author
  • Myron Yaster
    Affiliations
    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Yuan-Xiang Tao
    Correspondence
    Address reprint requests to Yuan-Xiang Tao, MD, PhD, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 1721 East Madison St, 370 Ross, Baltimore, MD 21205.
    Affiliations
    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author

      Abstract

      Voltage-gated sodium channels (Nav) are essential for the generation and conduction of action potentials. Peripheral inflammation increases the expression of Nav1.7 and Nav1.8 in dorsal root ganglion (DRG) neurons, suggesting that they participate in the induction and maintenance of chronic inflammatory pain. However, how Nav1.7 and Nav1.8 are regulated in the DRG under inflammatory pain conditions remains unclear. Using a complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model and Western blot analysis, we found that phosphorylated Akt (p-Akt) was significantly increased in the ipsilateral L4/5 DRGs of rats on days 3 and 7 after intraplantar CFA injection. Immunohistochemistry showed that the percentage of p-Akt-positive neurons in the DRG was also significantly increased in the ipsilateral L4/5 DRGs at these time points. Moreover, CFA injection increased the colocalization of p-Akt with Nav1.7 and Nav1.8 in L4/5 DRG neurons. Pretreatment of rats with an intrathecal injection of Akt inhibitor IV blocked CFA-induced thermal hyperalgesia and CFA-induced increases in Nav1.7 and Nav1.8 in the L4/5 DRGs on day 7 after CFA injection. Our findings suggest that the Akt pathway participates in inflammation-induced upregulation of Nav1.7 and Nav1.8 expression in DRG neurons. This participation might contribute to the maintenance of chronic inflammatory pain.

      Perspective

      This article presents that inhibition of Akt blocks CFA-induced thermal hyperalgesia and CFA-induced increases in dorsal root ganglion Nav1.7 and Nav1.8. These findings have potential implications for use of Akt inhibitors to prevent and/or treat persistent inflammatory pain.

      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

        • Akopian A.N.
        • Souslova V.
        • England S.
        • Okuse K.
        • Ogata N.
        • Ure J.
        • Smith A.
        • Kerr B.J.
        • McMahon S.B.
        • Boyce S.
        • Hill R.
        • Stanfa L.C.
        • Dickenson A.H.
        • Wood J.N.
        The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.
        Nat Neurosci. 1999; 2: 541-548
        • Asante C.O.
        • Wallace V.C.
        • Dickenson A.H.
        Formalin-induced behavioural hypersensitivity and neuronal hyperexcitability are mediated by rapid protein synthesis at the spinal level.
        Mol Pain. 2009; 5: 27
        • Bhaskar P.T.
        • Hay N.
        The two TORCs and Akt.
        Dev Cell. 2007; 12: 487-502
        • Black J.A.
        • Dib-Hajj S.
        • McNabola K.
        • Jeste S.
        • Rizzo M.A.
        • Kocsis J.D.
        • Waxman S.G.
        Spinal sensory neurons express multiple sodium channel alpha-subunit mRNAs.
        Brain Res Mol Brain Res. 1996; 43: 117-131
        • Black J.A.
        • Frezel N.
        • Dib-Hajj S.D.
        • Waxman S.G.
        Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn.
        Mol Pain. 2012; 8: 82
        • Black J.A.
        • Liu S.
        • Tanaka M.
        • Cummins T.R.
        • Waxman S.G.
        Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain.
        Pain. 2004; 108: 237-247
        • Boreddy S.R.
        • Pramanik K.C.
        • Srivastava S.K.
        Pancreatic tumor suppression by benzyl isothiocyanate is associated with inhibition of PI3K/AKT/FOXO pathway.
        Clin Cancer Res. 2011; 17: 1784-1795
        • Coggeshall R.E.
        • Tate S.
        • Carlton S.M.
        Differential expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 in normal and inflamed rats.
        Neurosci Lett. 2004; 355: 45-48
        • Dib-Hajj S.D.
        • Cummins T.R.
        • Black J.A.
        • Waxman S.G.
        Sodium channels in normal and pathological pain.
        Annu Rev Neurosci. 2010; 33: 325-347
        • Djouhri L.
        • Fang X.
        • Okuse K.
        • Wood J.N.
        • Berry C.M.
        • Lawson S.N.
        The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons.
        J Physiol. 2003; 550: 739-752
        • Djouhri L.
        • Newton R.
        • Levinson S.R.
        • Berry C.M.
        • Carruthers B.
        • Lawson S.N.
        Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Nav 1.7 (PN1) Na+ channel alpha subunit protein.
        J Physiol. 2003; 546: 565-576
        • England S.
        • Bevan S.
        • Docherty R.J.
        PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade.
        J Physiol. 1996; 495: 429-440
        • Gao Y.J.
        • Xu Z.Z.
        • Liu Y.C.
        • Wen Y.R.
        • Decosterd I.
        • Ji R.R.
        The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition.
        Pain. 2010; 148: 309-319
        • Geranton S.M.
        • Jimenez-Diaz L.
        • Torsney C.
        • Tochiki K.K.
        • Stuart S.A.
        • Leith J.L.
        • Lumb B.M.
        • Hunt S.P.
        A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states.
        J Neurosci. 2009; 29: 15017-15027
        • Gold M.S.
        • Levine J.D.
        • Correa A.M.
        Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro.
        J Neurosci. 1998; 18: 10345-10355
        • Gould III, H.J.
        • England J.D.
        • Soignier R.D.
        • Nolan P.
        • Minor L.D.
        • Liu Z.P.
        • Levinson S.R.
        • Paul D.
        Ibuprofen blocks changes in Na v. 1.7 and 1.8 sodium channels associated with complete Freund's adjuvant-induced inflammation in rat.
        J Pain. 2004; 5: 270-280
        • Jaworski J.
        • Sheng M.
        The growing role of mTOR in neuronal development and plasticity.
        Mol Neurobiol. 2006; 34: 205-219
        • Jeon S.J.
        • Han S.H.
        • Yang S.I.
        • Choi J.W.
        • Kwon K.J.
        • Park S.H.
        • Kim H.Y.
        • Cheong J.H.
        • Ryu J.H.
        • Ko K.H.
        • Wells D.G.
        • Shin C.Y.
        Positive feedback regulation of Akt-FMRP pathway protects neurons from cell death.
        J Neurochem. 2012; 123: 226-238
        • Jimenez-Diaz L.
        • Geranton S.M.
        • Passmore G.M.
        • Leith J.L.
        • Fisher A.S.
        • Berliocchi L.
        • Sivasubramaniam A.K.
        • Sheasby A.
        • Lumb B.M.
        • Hunt S.P.
        Local translation in primary afferent fibers regulates nociception.
        PLoS ONE. 2008; 3: e1961
        • Joshi S.K.
        • Mikusa J.P.
        • Hernandez G.
        • Baker S.
        • Shieh C.C.
        • Neelands T.
        • Zhang X.F.
        • Niforatos W.
        • Kage K.
        • Han P.
        • Krafte D.
        • Faltynek C.
        • Sullivan J.P.
        • Jarvis M.F.
        • Honore P.
        Involvement of the TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative, pain states.
        Pain. 2006; 123: 75-82
        • Karpova A.
        • Sanna P.P.
        • Behnisch T.
        Involvement of multiple phosphatidylinositol 3-kinase-dependent pathways in the persistence of late-phase long term potentiation expression.
        Neuroscience. 2006; 137: 833-841
        • Latremoliere A.
        • Woolf C.J.
        Central sensitization: a generator of pain hypersensitivity by central neural plasticity.
        J Pain. 2009; 10: 895-926
        • Nassar M.A.
        • Stirling L.C.
        • Forlani G.
        • Baker M.D.
        • Matthews E.A.
        • Dickenson A.H.
        • Wood J.N.
        Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain.
        Proc Natl Acad Sci U S A. 2004; 101: 12706-12711
        • Okuse K.
        • Chaplan S.R.
        • McMahon S.B.
        • Luo Z.D.
        • Calcutt N.A.
        • Scott B.P.
        • Akopian A.N.
        • Wood J.N.
        Regulation of expression of the sensory neuron-specific sodium channel SNS in inflammatory and neuropathic pain.
        Mol Cell Neurosci. 1997; 10: 196-207
        • Park J.S.
        • Voitenko N.
        • Petralia R.S.
        • Guan X.
        • Xu J.T.
        • Steinberg J.P.
        • Takamiya K.
        • Sotnik A.
        • Kopach O.
        • Huganir R.L.
        • Tao Y.X.
        Persistent inflammation induces GluR2 internalization via NMDA receptor-triggered PKC activation in dorsal horn neurons.
        J Neurosci. 2009; 29: 3206-3219
        • Park J.S.
        • Yaster M.
        • Guan X.
        • Xu J.T.
        • Shih M.H.
        • Guan Y.
        • Raja S.N.
        • Tao Y.X.
        Role of spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in complete Freund's adjuvant-induced inflammatory pain.
        Mol Pain. 2008; 4: 67
        • Pezet S.
        • Spyropoulos A.
        • Williams R.J.
        • McMahon S.B.
        Activity-dependent phosphorylation of Akt/PKB in adult DRG neurons.
        Eur J Neurosci. 2005; 21: 1785-1797
        • Price T.J.
        • Rashid M.H.
        • Millecamps M.
        • Sanoja R.
        • Entrena J.M.
        • Cervero F.
        Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR.
        J Neurosci. 2007; 27: 13958-13967
        • Sanna P.P.
        • Cammalleri M.
        • Berton F.
        • Simpson C.
        • Lutjens R.
        • Bloom F.E.
        • Francesconi W.
        Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region.
        J Neurosci. 2002; 22: 3359-3365
        • Shi T.J.
        • Huang P.
        • Mulder J.
        • Ceccatelli S.
        • Hokfelt T.
        Expression of p-Akt in sensory neurons and spinal cord after peripheral nerve injury.
        Neurosignals. 2009; 17: 203-212
        • Shih M.H.
        • Kao S.C.
        • Wang W.
        • Yaster M.
        • Tao Y.X.
        Spinal cord NMDA receptor-mediated activation of mammalian target of rapamycin is required for the development and maintenance of bone cancer-induced pain hypersensitivities in rats.
        J Pain. 2012; 13: 338-349
        • Shim Y.J.
        • Kang B.H.
        • Jeon H.S.
        • Park I.S.
        • Lee K.U.
        • Lee I.K.
        • Park G.H.
        • Lee K.M.
        • Schedin P.
        • Min B.H.
        Clusterin induces matrix metalloproteinase-9 expression via ERK1/2 and PI3K/Akt/NF-kappaB pathways in monocytes/macrophages.
        J Leukoc Biol. 2011; 90: 761-769
        • Strickland I.T.
        • Martindale J.C.
        • Woodhams P.L.
        • Reeve A.J.
        • Chessell I.P.
        • McQueen D.S.
        Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.
        Eur J Pain. 2008; 12: 564-572
        • Sun R.Q.
        • Tu Y.J.
        • Yan J.Y.
        • Willis W.D.
        Activation of protein kinase B/Akt signaling pathway contributes to mechanical hypersensitivity induced by capsaicin.
        Pain. 2006; 120: 86-96
        • Tanaka M.
        • Cummins T.R.
        • Ishikawa K.
        • Dib-Hajj S.D.
        • Black J.A.
        • Waxman S.G.
        SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model.
        Neuroreport. 1998; 9: 967-972
        • Tao Y.X.
        • Hassan A.
        • Haddad E.
        • Johns R.A.
        Expression and action of cyclic GMP-dependent protein kinase Ialpha in inflammatory hyperalgesia in rat spinal cord.
        Neuroscience. 2000; 95: 525-533
        • Tao Y.X.
        • Huang Y.Z.
        • Mei L.
        • Johns R.A.
        Expression of PSD-95/SAP90 is critical for N-methyl-D-aspartate receptor-mediated thermal hyperalgesia in the spinal cord.
        Neuroscience. 2000; 98: 201-206
        • Tao Y.X.
        • Johns R.A.
        Effect of the deficiency of spinal PSD-95/SAP90 on the minimum alveolar anesthetic concentration of isoflurane in rats.
        Anesthesiology. 2001; 94: 1010-1015
        • Tao Y.X.
        • Johns R.A.
        Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw.
        Neuroscience. 2002; 112: 439-446
        • Tate S.
        • Benn S.
        • Hick C.
        • Trezise D.
        • John V.
        • Mannion R.J.
        • Costigan M.
        • Plumpton C.
        • Grose D.
        • Gladwell Z.
        • Kendall G.
        • Dale K.
        • Bountra C.
        • Woolf C.J.
        Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons.
        Nat Neurosci. 1998; 1: 653-655
        • Waxman S.G.
        • Cummins T.R.
        • Dib-Hajj S.
        • Fjell J.
        • Black J.A.
        Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain.
        Muscle Nerve. 1999; 22: 1177-1187
        • Xu J.T.
        • Tu H.Y.
        • Xin W.J.
        • Liu X.G.
        • Zhang G.H.
        • Zhai C.H.
        Activation of phosphatidylinositol 3-kinase and protein kinase B/Akt in dorsal root ganglia and spinal cord contributes to the neuropathic pain induced by spinal nerve ligation in rats.
        Exp Neurol. 2007; 206: 269-279
        • Xu J.T.
        • Zhao X.
        • Yaster M.
        • Tao Y.X.
        Expression and distribution of mTOR, p70S6K, 4E-BP1, and their phosphorylated counterparts in rat dorsal root ganglion and spinal cord dorsal horn.
        Brain Res. 2010; 1336: 46-57
        • Xu Q.
        • Fitzsimmons B.
        • Steinauer J.
        • O'Neill A.
        • Newton A.C.
        • Hua X.Y.
        • Yaksh T.L.
        Spinal phosphinositide 3-kinase-Akt-mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesia.
        J Neurosci. 2011; 31: 2113-2124
        • Yeomans D.C.
        • Levinson S.R.
        • Peters M.C.
        • Koszowski A.G.
        • Tzabazis A.Z.
        • Gilly W.F.
        • Wilson S.P.
        Decrease in inflammatory hyperalgesia by herpes vector-mediated knockdown of Nav1.7 sodium channels in primary afferents.
        Hum Gene Ther. 2005; 16: 271-277
        • Zhuang Z.Y.
        • Xu H.
        • Clapham D.E.
        • Ji R.R.
        Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization.
        J Neurosci. 2004; 24: 8300-8309