Advertisement

Enhanced Excitability and Down-Regulated Voltage-Gated Potassium Channels in Colonic DRG Neurons from Neonatal Maternal Separation Rats

Published:February 07, 2011DOI:https://doi.org/10.1016/j.jpain.2010.11.005

      Abstract

      Irritable bowel syndrome (IBS), characterized mainly by abdominal pain, is a functional bowel disorder. The present study aimed to examine changes in the excitability and the activity of the voltage-gated K+ channel in dorsal root ganglia (DRG) neurons innervating the colon of rats subjected to neonatal maternal separation (NMS). Colonic DRG neurons from NMS rats as identified by FAST DiI™ labeling showed an increased cell size compared with those from nonhandled (NH) rats. Whole cell current-clamp recordings showed that colonic DRG neurons from NMS rats displayed: 1) depolarized resting membrane potential; 2) increased input resistance; 3) a dramatic reduction in rheobase; and 4) a significant increase in the number of action potentials evoked at twice rheobase. Whole cell voltage-clamp recordings revealed that neurons from both groups exhibited transient A-type (IA) and delayed rectifier (IK) K+ currents. Compared with NH rat neurons, the averaged density of IK was significantly reduced in NMS rat neurons. Furthermore, the Kv1.2 expression was significantly decreased in NMS rat colonic DRG neurons. These results suggest that NMS increases the excitability of colonic DRG neurons mainly by suppressing the IK current, which is likely accounted for by the downregulation of the Kv1.2 expression and somal hypertrophy.

      Perspective

      This study demonstrates the alteration of delayed rectifier K current and Kv1.2 expression in DRG neurons from IBS model rats, representing a molecular mechanism underlying visceral pain and sensitization in IBS, suggesting the potential of Kv1.2 as a therapeutic target for the treatment of IBS.

      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

        • Akins P.T.
        • McCleskey E.W.
        Characterization of potassium currents in adult rat sensory neurons and modulation by opioids and cyclic AMP.
        Neuroscience. 1993; 56: 759-769
        • Barreau F.
        • Ferrier L.
        • Fioramonti J.
        • Bueno L.
        Neonatal maternal deprivation triggers long term alterations in colonic epithelial barrier and mucosal immunity in rats.
        Gut. 2004; 53: 501-506
        • Bekkers J.M.
        • Delaney A.J.
        Modulation of excitability by alpha-dendrotoxin- sensitive potassium channels in neocortical pyramidal neurons.
        J Neurosci. 2001; 21: 6553-6560
        • Beyak M.J.
        • Ramji N.
        • Krol K.M.
        • Kawaja M.D.
        • Vanner S.J.
        Two TTX-resistant Na+ currents in mouse colonic dorsal root ganglia neurons and their role in colitis-induced hyperexcitability.
        Am J Physiol Gastrointest Liver Physiol. 2004; 287: G845-855
        • Beyak M.J.
        • Vanner S.
        Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurones: The role of voltage-gated ion channels.
        Neurogastroenterol Motil. 2005; 17: 175-186
        • Blackshaw L.A.
        • Gebhart G.F.
        The pharmacology of gastrointestinal nociceptive pathways.
        Curr Opin Pharmacol. 2002; 2: 642-649
        • Bradesi S.
        • Herman J.
        • Mayer E.A.
        Visceral analgesics: Drugs with a great potential in functional disorders?.
        Curr Opin Pharmacol. 2008; 8: 697-703
        • Brierley S.M.
        • Carter R.
        • Jones 3rd, W.
        • Xu L.
        • Robinson D.R.
        • Hicks G.A.
        • Gebhart G.F.
        • Blackshaw L.A.
        Differential chemosensory function and receptor expression of splanchnic and pelvic colonic afferents in mice.
        J Physiol. 2005; 567: 267-281
        • Chien L.Y.
        • Cheng J.K.
        • Chu D.
        • Cheng C.F.
        • Tsaur M.L.
        Reduced expression of A-type potassium channels in primary sensory neurons induces mechanical hypersensitivity.
        J Neurosci. 2007; 27: 9855-9865
        • Christoph T.
        • Gillen C.
        • Mika J.
        • Grunweller A.
        • Schafer M.K.
        • Schiene K.
        • Frank R.
        • Jostock R.
        • Bahrenberg G.
        • Weihe E.
        • Erdmann V.A.
        • Kurreck J.
        Antinociceptive effect of antisense oligonucleotides against the vanilloid receptor VR1/TRPV1.
        Neurochem Int. 2007; 50: 281-290
        • Chung E.K.
        • Zhang X.
        • Li Z.
        • Zhang H.
        • Xu H.
        • Bian Z.
        Neonatal maternal separation enhances central sensitivity to noxious colorectal distention in rat.
        Brain Res. 2007; 1153: 68-77
        • Chung E.K.
        • Zhang X.J.
        • Xu H.X.
        • Sung J.J.
        • Bian Z.X.
        Visceral hyperalgesia induced by neonatal maternal separation is associated with nerve growth factor-mediated central neuronal plasticity in rat spinal cord.
        Neuroscience. 2007; 149: 685-695
        • Coetzee W.A.
        • Amarillo Y.
        • Chiu J.
        • Chow A.
        • Lau D.
        • McCormack T.
        • Moreno H.
        • Nadal M.S.
        • Ozaita A.
        • Pountney D.
        • Saganich M.
        Vega-Saenz de Miera E, Rudy B: Molecular diversity of K+ channels.
        Ann N Y Acad Sci. 1999; 868: 233-285
        • Coutinho S.V.
        • Plotsky P.M.
        • Sablad M.
        • Miller J.C.
        • Zhou H.
        • Bayati A.I.
        • McRoberts J.A.
        • Mayer E.A.
        Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat.
        Am J Physiol Gastrointest Liver Physiol. 2002; 282: G307-316
        • Dang K.
        • Bielefeldt K.
        • Gebhart G.F.
        Gastric ulcers reduce A-type potassium currents in rat gastric sensory ganglion neurons.
        Am J Physiol Gastrointest Liver Physiol. 2004; 286: G573-579
        • Delvaux M.
        Role of visceral sensitivity in the pathophysiology of irritable bowel syndrome.
        Gut. 2002; 51: i67-i71
        • Everill B.
        • Kocsis J.D.
        Reduction in potassium currents in identified cutaneous afferent dorsal root ganglion neurons after axotomy.
        J Neurophysiol. 1999; 82: 700-708
        • Flake N.M.
        • Bonebreak D.B.
        • Gold M.S.
        Estrogen and inflammation increase the excitability of rat temporomandibular joint afferent neurons.
        J Neurophysiol. 2005; 93: 1585-1597
        • Gareau M.G.
        • Jury J.
        • Yang P.C.
        • MacQueen G.
        • Perdue M.H.
        Neonatal maternal separation causes colonic dysfunction in rat pups including impaired host resistance.
        Pediatr Res. 2006; 59: 83-88
        • Glazebrook P.A.
        • Ramirez A.N.
        • Schild J.H.
        • Shieh C.C.
        • Doan T.
        • Wible B.A.
        • Kunze D.L.
        Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons.
        J Physiol. 2002; 541: 467-482
        • Gold M.S.
        • Traub R.J.
        Cutaneous and colonic rat DRG neurons differ with respect to both baseline and PGE2-induced changes in passive and active electrophysiological properties.
        J Neurophysiol. 2004; 91: 2524-2531
        • Hsiao C.F.
        • Kaur G.
        • Vong A.
        • Bawa H.
        • Chandler S.H.
        Participation of Kv1 channels in control of membrane excitability and burst generation in mesencephalic V neurons.
        J Neurophysiol. 2009; 101: 1407-1418
        • Ishikawa K.
        • Tanaka M.
        • Black J.A.
        • Waxman S.G.
        Changes in expression of voltage-gated potassium channels in dorsal root ganglion neurons following axotomy.
        Muscle Nerve. 1999; 22: 502-507
        • Kayssi A.
        • Amadesi S.
        • Bautista F.
        • Bunnett N.W.
        • Vanner S.
        Mechanisms of protease-activated receptor 2-evoked hyperexcitability of nociceptive neurons innervating the mouse colon.
        J Physiol. 2007; 580: 977-991
        • 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
        • Lu S.G.
        • Gold M.S.
        Inflammation-induced increase in evoked calcium transients in subpopulations of rat dorsal root ganglion neurons.
        Neuroscience. 2008; 153: 279-288
        • Luo J.
        • Yin G.F.
        • Gu Y.Z.
        • Liu Y.
        • Dai J.P.
        • Li C.
        • Li Z.W.
        Characterization of three types of ATP-activated current in relation to P2X subunits in rat trigeminal ganglion neurons.
        Brain Res. 2006; 1115: 9-15
        • Moore B.A.
        • Stewart T.M.
        • Hill C.
        • Vanner S.J.
        TNBS ileitis evokes hyperexcitability and changes in ionic membrane properties of nociceptive DRG neurons.
        Am J Physiol Gastrointest Liver Physiol. 2002; 282: G1045-1051
        • Park S.Y.
        • Choi J.Y.
        • Kim R.U.
        • Lee Y.S.
        • Cho H.J.
        • Kim D.S.
        Downregulation of voltage-gated potassium channel alpha gene expression by axotomy and neurotrophins in rat dorsal root ganglia.
        Mol Cells. 2003; 16: 256-259
        • Pongs O.
        Regulation of excitability by potassium channels.
        Results Probl Cell Differ. 2008; 44: 145-161
        • Qian A.H.
        • Liu X.Q.
        • Yao W.Y.
        • Wang H.Y.
        • Sun J.
        • Zhou L.
        • Yuan Y.Z.
        Voltage-gated potassium channels in IB4-positive colonic sensory neurons mediate visceral hypersensitivity in the rat.
        Am J Gastroenterol. 2009; 104: 2014-2027
        • Rasband M.N.
        • Park E.W.
        • Vanderah T.W.
        • Lai J.
        • Porreca F.
        • Trimmer J.S.
        Distinct potassium channels on pain-sensing neurons.
        Proc Natl Acad Sci U S A. 2001; 98: 13373-13378
        • Sandler R.S.
        • Drossman D.A.
        • Nathan H.P.
        • McKee D.C.
        Symptom complaints and health care seeking behavior in subjects with bowel dysfunction.
        Gastroenterology. 1984; 87: 314-318
        • Sculptoreanu A.
        • de Groat W.C.
        • Buffington C.A.
        • Birder L.A.
        Abnormal excitability in capsaicin-responsive DRG neurons from cats with feline interstitial cystitis.
        Exp Neurol. 2005; 193: 437-443
        • Sculptoreanu A.
        • Artim D.E.
        • de Groat W.C.
        Neurokinins inhibit low threshold inactivating K+ currents in capsaicin responsive DRG neurons.
        Exp Neurol. 2009; 219: 562-573
        • Shen W.
        • Hernandez-Lopez S.
        • Tkatch T.
        • Held J.E.
        • Surmeier D.J.
        Kv1.2-containing K+ channels regulate subthreshold excitability of striatal medium spiny neurons.
        J Neurophysiol. 2004; 91: 1337-1349
        • Stacher G.
        • Christensen J.
        Visceral hypersensitivity in irritable bowel syndrome: A summary review.
        Dig Dis Sci. 2006; 51: 440-445
        • Steers W.D.
        • Ciambotti J.
        • Etzel B.
        • Erdman S.
        • de Groat W.C.
        Alterations in afferent pathways from the urinary bladder of the rat in response to partial urethral obstruction.
        J Comp Neurol. 1991; 310: 401-410
        • Steers W.D.
        • Kolbeck S.
        • Creedon D.
        • Tuttle J.B.
        Nerve growth factor in the urinary bladder of the adult regulates neuronal form and function.
        J Clin Invest. 1991; 88: 1709-1715
        • Stewart T.
        • Beyak M.J.
        • Vanner S.
        Ileitis modulates potassium and sodium currents in guinea pig dorsal root ganglia sensory neurons.
        J Physiol. 2003; 552: 797-807
        • Trimmer J.S.
        • Rhodes K.J.
        Localization of voltage-gated ion channels in mammalian brain.
        Annu Rev Physiol. 2004; 66: 477-519
        • Verne G.N.
        • Robinson M.E.
        • Price D.D.
        Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome.
        Pain. 2001; 93: 7-14
        • Wang H.
        • Kunkel D.D.
        • Martin T.M.
        • Schwartzkroin P.A.
        • Tempel B.L.
        Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons.
        Nature. 1993; 365: 75-79
        • Winston J.H.
        • He Z.J.
        • Shenoy M.
        • Xiao S.Y.
        • Pasricha P.J.
        Molecular and behavioral changes in nociception in a novel rat model of chronic pancreatitis for the study of pain.
        Pain. 2005; 117: 214-222
        • Woolf C.J.
        • Safieh-Garabedian B.
        • Ma Q.P.
        • Crilly P.
        • Winter J.
        Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity.
        Neuroscience. 1994; 62: 327-331
        • Xu G.Y.
        • Winston J.H.
        • Shenoy M.
        • Yin H.
        • Pasricha P.J.
        Enhanced excitability and suppression of A-type K+ current of pancreas-specific afferent neurons in a rat model of chronic pancreatitis.
        Am J Physiol Gastrointest Liver Physiol. 2006; 291: G424-431
        • Yang E.K.
        • Takimoto K.
        • Hayashi Y.
        • de Groat W.C.
        • Yoshimura N.
        Altered expression of potassium channel subunit mRNA and alpha-dendrotoxin sensitivity of potassium currents in rat dorsal root ganglion neurons after axotomy.
        Neuroscience. 2004; 123: 867-874
        • Yoshimura N.
        • de Groat W.C.
        Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation.
        J Neurosci. 1999; 19: 4644-4653