Vol. 19, No. 3, 2011
Issue release date: August 2011
Free Access
Neurosignals 2011;19:142–150
(DOI:10.1159/000328311)
Original Paper
Add to my selection

Involvement of Subtypes γ and ε of Protein Kinase C in Colon Pain Induced by Formalin Injection

Zhang Y.a, b · Gong K.b, f · Zhou W.c · Shao G.d · Li S.e · Lin Q.f · Li J.b
aDepartment of Neurology, the Affiliated Hospital of Taishan Medical College, Tai’an, bDepartment of Neurobiology, Capital Medical University, Beijing, cDepartment of Biochemistry, Jishou University School of Medicine, Jishou, dBiomedical Research Centre, Baotou Medical College, Baotou, and eDepartment of Emergency, Xuanwu Hospital, Capital Medical University, Beijing, China; fDepartment of Psychology, University of Texas at Arlington, Arlington, Tex., USA
email Corresponding Author


 goto top of outline Key Words

  • Visceral pain
  • Protein kinase C
  • Formalin
  • Colon
  • Wide dynamic range neuron

 goto top of outline Abstract

Protein kinase C (PKC) has been widely reported to participate in somatic pain; however, its role in visceral pain remains largely unclear. Using a colon inflammatory pain model by intracolonic injection of formalin in rats, the present study was to examine the role of PKC in visceral pain and determine which subtypes may be involved. The colon pain behavior induced by formalin injection could be enhanced by intrathecal pretreatment with a PKC activator (PMA), and alleviated by a PKC inhibitor (H-7). Wide dynamic range (WDR) neurons in the L6-S1 spinal dorsal horn that were responsive to colorectal distension were recorded extracellularly. It was found that neuronal activity was greatly increased following formalin injection. Microdialysis of PMA near the recorded neuron in the spinal dorsal horn facilitated the enhanced responsive activity induced by formalin injection, while H-7 inhibited significantly the enhanced response induced by formalin injection. Western blot analysis revealed that membrane translocation of PKC-γ and PKC-ε, but not other subtypes, in the spinal cord was obviously increased following formalin injection. Therefore, our findings suggest that PKC is actively involved in the colon pain induced by intracolonic injection of formalin. PKC-γ and PKC-ε subtypes seem to significantly contribute to this process.

Copyright © 2011 S. Karger AG, Basel


 goto top of outline References
  1. Malmberg AB, Chen C, Tonegawa S, Basbaum AI: Preserved acute pain and reduced neuropathic pain in mice lacking PKC-gamma. Science 1997;278:279–283.
  2. Malmberg AB: Protein kinase subtypes involved in injury-induced nociception. Prog Brain Res 2000;129:51–59.
  3. Mao J, Price DD, Mayer DJ, Hayes RL: Pain-related increases in spinal cord membrane-bound protein kinase C following peripheral nerve injury. Brain Res 1992;588:144–149.
  4. Park JS, Voitenko N, Petralia RS, Guan X, Xu JT, Steinberg JP, Takamiya K, Sotnik A, Kopach O, Huganir RL, Tao YX: Persistent inflammation induces GluR2 internalization via NMDA receptor-triggered PKC activation in dorsal horn neurons. J Neurosci 2009;29:3206–3219.
  5. Xiaoping G, Xiaofang Z, Yaguo Z, Juan Z, Junhua W, Zhengliang M: Involvement of the spinal NMDA receptor/PKC-gamma signaling pathway in the development of bone cancer pain. Brain Res 2010;1335:83–90.

    External Resources

  6. Xu X, Wang P, Zou X, Li D, Fang L, Gong K, Lin Q: The effects of sympathetic outflow on upregulation of vanilloid receptors TRPV(1) in primary afferent neurons evoked by intradermal capsaicin. Exp Neurol 2010;222:93–107.
  7. Yashpal K, Fisher K, Chabot JG, Coderre TJ: Differential effects of NMDA and group I mGluR antagonists on both nociception and spinal cord protein kinase C translocation in the formalin test and a model of neuropathic pain in rats. Pain 2001;94:17–29.
  8. Mellor H, Parker PJ: The extended protein kinase C superfamily. Biochem J 1998;332:281–292.
  9. Han JS, Neugebauer V: Synaptic plasticity in the amygdala in a visceral pain model in rats. Neurosci Lett 2004;361:254–257.
  10. Laird JM, Martinez-Caro L, Garcia-Nicas E, Cervero F: A new model of visceral pain and referred hyperalgesia in the mouse. Pain 2001;92:335–342.
  11. Qin C, Malykhina AP, Akbarali HI, Foreman RD: Cross-organ sensitization of lumbosacral spinal neurons receiving urinary bladder input in rats with inflamed colon. Gastroenterology 2005;129:1967–1978.

    External Resources

  12. Miampamba M, Chery-Croze S, Gorry F, Berger F, Chayvialle JA: Inflammation of the colonic wall induced by formalin as a model of acute visceral pain. Pain 1994;57:327–334.
  13. Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983;16:109–110.
  14. Yaksh TL, Rudy TA: Chronic catheterization of the spinal subarachnoid space. Physiol Behav 1976;17:1031–1036.
  15. Coderre TJ: Contribution of protein kinase C to central sensitization and persistent pain following tissue injury. Neurosci Lett 1992;140:181–184.
  16. Coutinho SV, Meller ST, Gebhart GF: Intracolonic zymosan produces visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-NMDA receptors. Brain Res 1996;736:7–15.
  17. Traub RJ, Wang G: Colonic inflammation decreases thermal sensitivity of the forepaw and hindpaw in the rat. Neurosci Lett 2004;359:81–84.
  18. Miampamba M, Chery-Croze S, tolle-Sarbach S, Guez D, Chayvialle JA: Antinociceptive effects of oral clonidine and S12813–4 in acute colon inflammation in rats. Eur J Pharmacol 1996;308:251–259.
  19. Miampamba M, Sharkey AK: c-Fos expression in the myenteric plexus, spinal cord and brainstem following injection of formalin in the rat colonic wall. J Auton Nerv Syst 1999;77:140–151.
  20. Miampamba M, Chery-Croze S, Chayvialle JA: Spinal and intestinal levels of substance P, calcitonin gene-related peptide and vasoactive intestinal polypeptide following perendoscopic injection of formalin in rat colonic wall. Neuropeptides 1992;22:73–80.
  21. Cervero F, Janig W: Visceral nociceptors: a new world order? Trends Neurosci 1992;15:374–378.
  22. Cervero F: Visceral pain: mechanisms of peripheral and central sensitization. Ann Med 1995;27:235–239.
  23. Malmberg AB, Yaksh TL: The effect of morphine on formalin-evoked behaviour and spinal release of excitatory amino acids and prostaglandin E2 using microdialysis in conscious rats. Br J Pharmacol 1995;114:1069–1075.
  24. Vetter G, Geisslinger G, Tegeder I: Release of glutamate, nitric oxide and prostaglandin E2 and metabolic activity in the spinal cord of rats following peripheral nociceptive stimulation. Pain 2001;92:213–218.
  25. Sorkin LS, McAdoo DJ: Amino acids and serotonin are released into the lumbar spinal cord of the anesthetized cat following intradermal capsaicin injections. Brain Res 1993;607:89–98.
  26. Mayer ML, Miller RJ: Excitatory amino acid receptors, second messengers and regulation of intracellular Ca2+ in mammalian neurons. Trends Pharmacol Sci 1990;11:254–260.
  27. Nishizuka Y: The Albert Lasker Medical Awards: the family of protein kinase C for signal transduction. JAMA 1989;262:1826–1833.
  28. Lan JY, Skeberdis VA, Jover T, Grooms SY, Lin Y, Araneda RC, Zheng X, Bennett MV, Zukin RS: Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci 2001;4:382–390.
  29. Palecek J, Paleckova V, Willis WD: Postsynaptic dorsal column neurons express NK1 receptors following colon inflammation. Neuroscience 2003;116:565–572.
  30. Cang CL, Zhang H, Zhang YQ, Zhao ZQ: PKC-epsilon-dependent potentiation of TTX-resistant Nav1.8 current by neurokinin-1 receptor activation in rat dorsal root ganglion neurons. Mol Pain 2009;5:33.

    External Resources

  31. Moore BA, Stewart TM, Hill C, Vanner SJ: TNBS ileitis evokes hyperexcitability and changes in ionic membrane properties of nociceptive DRG neurons. Am J Physiol Gastrointest Liver Physiol 2002;282:G1045–G1051.
  32. Bielefeldt K, Ozaki N, Gebhart GF: Mild gastritis alters voltage-sensitive sodium currents in gastric sensory neurons in rats. Gastroenterology 2002;122:752–761.
  33. Huang TY, Belzer V, Hanani M: Gap junctions in dorsal root ganglia: possible contribution to visceral pain. Eur J Pain 2010;14:49–11.
  34. Bilsky EJ, Bernstein RN, Wang ZJ, Sadee W, Porreca F: Effects of naloxone and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 and the protein kinase inhibitors H7 and H8 on acute morphine dependence and antinociceptive tolerance in mice. J Pharmacol Exp Ther 1996;277:484–490.
  35. Balaban CD, Freilino M, Romero GG: Protein kinase C inhibition blocks the early appearance of vestibular compensation. Brain Res 1999;845:97–101.
  36. Choudhury GG: A linear signal transduction pathway involving phosphatidylinositol 3-kinase, protein kinase C epsilon, and MAPK in mesangial cells regulates interferon-gamma-induced STAT1 alpha transcriptional activation. J Biol Chem 2004;279:27399–27409.
  37. Howcroft TK, Tatum SM, Cosgrove JM, Lindquist RR: Protein kinase C (PKC) inhibitors inhibit primary (1–0) but not secondary (1–1) or cloned cytotoxic T lymphocytes. Biochem Biophys Res Commun 1988;154:1280–1286.
  38. Wright CD, Hoffman MD: The protein kinase C inhibitors H-7 and H-9 fail to inhibit human neutrophil activation. Biochem Biophys Res Commun 1986;135:749–755.
  39. Bie B, Pan ZZ: Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats. Mol Pain 2005;1:7.

    External Resources

  40. Chattopadhyay M, Mata M, Fink DJ: Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy. J Neurosci 2008;28:6652–6658.
  41. Correll CC, Phelps PT, Anthes JC, Umland S, Greenfeder S: Cloning and pharmacological characterization of mouse TRPV1. Neurosci Lett 2004;370:55–60.
  42. McFerran BW, Guild SB: Effects of protein kinase C activators upon the late stages of the ACTH secretory pathway of AtT-20 cells. Br J Pharmacol 1994;113:171–178.
  43. Coderre TJ: Contribution of protein kinase C to central sensitization and persistent pain following tissue injury. Neurosci Lett 1992;140:181–184.
  44. Sweitzer SM, Wong SM, Peters MC, Mochly-Rosen D, Yeomans DC, Kendig JJ: Protein kinase C epsilon and gamma: involvement in formalin-induced nociception in neonatal rats. J Pharmacol Exp Ther 2004;309:616–625.
  45. Furuta S, Shimizu T, Narita M, Matsumoto K, Kuzumaki N, Horie S, Suzuki T, Narita M: Subdiaphragmatic vagotomy promotes nociceptive sensitivity of deep tissue in rats. Neuroscience 2009;164:1252–1262.
  46. Khasar SG, Lin YH, Martin A, Dadgar J, McMahon T, Wang D, Hundle B, Aley KO, Isenberg W, McCarter G, Green PG, Hodge CW, Levine JD, Messing RO: A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice. Neuron 1999;24:253–260.
  47. Parada CA, Yeh JJ, Joseph EK, Levine JD: Tumor necrosis factor receptor type-1 in sensory neurons contributes to induction of chronic enhancement of inflammatory hyperalgesia in rat. Eur J Neurosci 2003;17:1847–1852.

    External Resources

  48. Aley KO, Messing RO, Mochly-Rosen D, Levine JD: Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J Neurosci 2000;20:4680–4685.
  49. Cesare P, Dekker LV, Sardini A, Parker PJ, McNaughton PA: Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. Neuron 1999;23:617–624.
  50. Burgess GM, Mullaney I, McNeill M, Dunn PM, Rang HP: Second messengers involved in the mechanism of action of bradykinin in sensory neurons in culture. J Neurosci 1989;9:3314–3325.
  51. Joseph EK, Bogen O, essandri-Haber N, Levine JD: PLC-beta 3 signals upstream of PKC epsilon in acute and chronic inflammatory hyperalgesia. Pain 2007;132:67–73.
  52. Numazaki M, Tominaga T, Toyooka H, Tominaga M: Direct phosphorylation of capsaicin receptor VR1 by protein kinase C-epsilon and identification of two target serine residues. J Biol Chem 2002;277:13375–13378.
  53. Dudek AZ, Zwolak P, Jasinski P, Terai K, Gallus NJ, Ericson ME, Farassati F: Protein kinase C-beta inhibitor enzastaurin (LY317615.HCI) enhances radiation control of murine breast cancer in an orthotopic model of bone metastasis. Invest New Drugs 2008;26:13–24.
  54. Yang L, Zhang FX, Huang F, Lu YJ, Li GD, Bao L, Xiao HS, Zhang X: Peripheral nerve injury induces trans-synaptic modification of channels, receptors and signal pathways in rat dorsal spinal cord. Eur J Neurosci 2004;19:871–883.
  55. Andratsch M, Mair N, Constantin CE, Scherbakov N, Benetti C, Quarta S, Vogl C, Sailer CA, Uceyler N, Brockhaus J, Martini R, Sommer C, Zeilhofer HU, Muller W, Kuner R, Davis JB, Rose-John S, Kress M: A key role for gp130 expressed on peripheral sensory nerves in pathological pain. J Neurosci 2009;29:13473–13483.

 goto top of outline Author Contacts

Jingjin Li
Department of Neurobiology
Capital Medical University
Beijing (China)
Tel. +86 10 8391 1490, E-Mail gc123321@126.com


 goto top of outline Article Information

Yanbo Zhang, Kerui Gong and Weihua Zhou contributed equally to this work.

Received: September 7, 2010
Accepted after revision: April 11, 2011
Published online: June 23, 2011
Number of Print Pages : 9
Number of Figures : 4, Number of Tables : 0, Number of References : 55


 goto top of outline Publication Details

Neurosignals

Vol. 19, No. 3, Year 2011 (Cover Date: August 2011)

Journal Editor: Ip N.Y. (Hong Kong)
ISSN: 1424-862X (Print), eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.