Skip to main content
Log in

Inhibition of the PKCγ-ε Pathway Relieves from Meningeal Nociception in an Animal Model: An Innovative Perspective for Migraine Therapy?

  • Original Article
  • Published:
Neurotherapeutics

Abstract

There is convincing evidence that nitric oxide (NO) may be a causative factor in the pathogenesis of migraine. We investigated the consequences of NO donors’ administration on meningeal processes related to the development of migraine pain in an animal model of meningeal nociception. The administration in mice of the NO donors nitroglycerin (GTN) and sodium nitroprusside (SNP) produced a delayed meningeal upregulation of interleukin-1ß and inducible NO synthase. A thermal allodynia and hyperalgesia devoid of side effects was produced 1 to 4 h after administration. To clarify the cellular pathways modulated by GTN and SNP, we examined the expression of cellular factors involved in pain modulation, such as protein kinase C (PKC) and its downstream effectors. Western blotting experiments showed an upregulation and increased phosphorylation of PKCγ and PKCε within dura mater after NO donors’ administration. A dramatic PKC-dependent increase of the phosphorylation of cyclic AMP response element binding protein (CREB) and signal transducer and activator of transcription (STAT)-1 was observed, along with an activation of the nuclear factor-κB (NF-κB) pathway, as reflected by a reduction of the inhibitory protein-κ-Bα (IκBα). Furthermore, the PKC blocker, Calphostin C, prevented the GTN and SNP-induced pain hypersensitivity. These results suggest the relevance of the PKC-mediated pathway in the induction of meningeal nociception and might help clarify the etiopathology of migraines. We can suggest PKC as a new target for migraine pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Olesen J. The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther 2008;120:157-171.

    Article  PubMed  CAS  Google Scholar 

  2. Iversen HK, Olesen J, Tfelt-Hansen P. Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 1989;38:17-24.

    Article  PubMed  CAS  Google Scholar 

  3. Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport 1993;4:1027-1030.

    Article  PubMed  CAS  Google Scholar 

  4. Christansen I, Thomsen LL, Daugaard D, Ulrich V, Olesen J. Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia 1999;19:660-667.

    Article  Google Scholar 

  5. Di Clemente L, Coppola G, Magis D, et al. Nitroglycerin sensitises in healthy subjects CNS structures involved in migraine pathophysiology: evidence from a study of nociceptive blink reflexes and visual evoked potentials. Pain 2009;144:156-161.

    Article  PubMed  Google Scholar 

  6. de Tommaso M, Guido M, Libro G, Sciruicchio V, Puca F. Zolmitriptan reverses blink reflex changes induced during the migraine attack in humans. Neurosci Lett 2000;289:57-60.

    Article  PubMed  Google Scholar 

  7. Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res 1995; 682:167-181.

    Article  PubMed  CAS  Google Scholar 

  8. Jones MG, Lever I, Bingham S, Read S, McMahon S, Parson A. Nitric oxide potentiates response of trigeminal neurons to dural or facial stimulation in the rat. Cephalalgia 2001;21:643-655.

    Article  PubMed  CAS  Google Scholar 

  9. Koulchitsky S, Fischer MJM, De Col R, Schlechtweg PM, Messlinger K. Biphasic response to nitric oxide of spinal trigeminal neurons with meningeal input in rat — possible implications for the pathophysiology of headaches. J Neurophysiol 2004;92:1320-1328.

    Article  PubMed  CAS  Google Scholar 

  10. Reuter U, Bolay H, Jansen-Olesen I, et al. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 2001;124:2490-502.

    Google Scholar 

  11. Velazquez KT, Mohammad H, Sweitzer SM. Protein kinase C in pain: involvement of multiple isoforms. Pharmacol Res 2007;55:578-589.

    Article  PubMed  CAS  Google Scholar 

  12. Bhatt KH, Pandey RK, Dahiya Y, Sodhi A. Protein kinase Cδ and protein tyrosine kin ase regulate peptidoglycan-induced nuclear factor-κB activation and inducible nitric oxide synthase expression in mouse peritoneal macrophages in vitro. Mol Immunol 2010;47:861-870.

    Article  PubMed  CAS  Google Scholar 

  13. Dieterle A, Fisher MJ, Link AS, Neuhuber WL, Messlinger K. Increase in CGRP- and nNOS-immunoreactive neurons in the rat trigeminal ganglion after infusion of an NO donor. J Cephalalagia 2011;31:31-42.

    Article  Google Scholar 

  14. Tassorelli C, Greco R, Wang D, Sandrini M, Sandrini G, Nappi G. Nitroglycerin induces hyperalgesia in rats – a time course study. Eur J Pharmacol 2003;464:159-162.

    Article  PubMed  CAS  Google Scholar 

  15. Galeotti N, Bartolini A, Ghelardini C. The phospholipase C-IP3 pathway is involved in muscarinic antinociception. Neuropsychopharmacology 2003;28:888-897.

    Article  PubMed  CAS  Google Scholar 

  16. Bank J. Migraine with aura after administration of sublingual nitroglycerin tablets. Headache 2001;41:84-87.

    Article  PubMed  CAS  Google Scholar 

  17. Harris JA. Using c-fos as marker of pain. Brain Res Bull 1998;45:1-8.

    Article  PubMed  CAS  Google Scholar 

  18. Giroux M, Descoteaux A. Cyclooxygenase-2 expression in macrophages: modulation by protein kinase C-α. J Immunol 2000;165:3985-3991.

    PubMed  CAS  Google Scholar 

  19. Foey AD, Brennan FM. Conventional protein kinase C and atypical protein kinase Cζ differentially regulate macrophage production of tumour necrosis factor-α and interleukin-10. Immunology 2004;112:44-53.

    Article  PubMed  CAS  Google Scholar 

  20. Chen CC, Wang JK, Lin SB. Antisense oligonucleotides targeting protein kinase C-α, -ßI, or -δ but not -η inhibit lipopolysaccharide-induced nitric oxide synthase expression in RAW 264.7 macrophages: involvement of a nuclear factor κB-dependent mechanism. J Immunol 1998;161:6206-6214.

    PubMed  CAS  Google Scholar 

  21. Pham TNQ, Brown BL, Dobson PRM, Richardson VJ. Protein kinase C-eta (PKC-ζ) is required for the development of inducible nitric oxide synthase (iNOS) positive phenotype in human monocytic cells. Nitric Oxide 2003;9:123-134.

    Article  PubMed  CAS  Google Scholar 

  22. Kang J, Yang M, Jou I, Joe E. Identification of protein kinase C isoforms involved in interferon-gamma-induced expression of inducible nitric oxide synthase in murine BV2 microglia. Neurosci Lett 2001;299:205-208.

    Article  PubMed  CAS  Google Scholar 

  23. Baltuch GH, Couldwell WT, Villemure JG, Yong VW. Protein kinase C inhibitors suppress cell growth in established and low-passage glioma cell lines: a comparison between staurosporine and tamoxifen. Neurosurgery 1993;33:495-501.

    Article  PubMed  CAS  Google Scholar 

  24. Powles TJ. Prevention of migrainous headaches by tamoxifen. Lancet 1986;2:1344.

    Article  PubMed  CAS  Google Scholar 

  25. Maggioni F, Palmieri A, Tropea M, Zanchin G. Influence of physiologic modification and of hormonal treatment in a patient with migraine with aura. J Headache Pain 2008;9:129-131.

    Article  PubMed  Google Scholar 

  26. Smitherman TA, Kolivas ED. Resolution of menstrually related migraine following aggressive treatment for breast cancer. Headache 2009; 50:485-496.

    Article  PubMed  Google Scholar 

  27. O’Dea JP, Davis EH. Tamoxifen in the treatment of menstrual migraine. Neurology 1990;40:1470-1471.

    Article  PubMed  Google Scholar 

  28. Cuzick J, Forbes JK, Sestak I, et al. Long-term results of tamoxifen prophylaxis for breast cancer – 96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 2007;99:272-282.

    Article  PubMed  CAS  Google Scholar 

  29. Ji RR, Rupp F. Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci 1997;17:1776-1785.

    PubMed  CAS  Google Scholar 

  30. Ma W, Quirion R. Increased phosphorylation of cyclic AMP response element-binding protein (CREB) in the superficial dorsal horn neurons following partial sciatic nerve ligation. Pain 2001;93:295-301.

    Article  PubMed  CAS  Google Scholar 

  31. Reuter U, Chiarugi A, Bolay H, Moskowitz MA. Nuclear factor-kappaB as a molecular target for migraine therapy. Ann Neurol 2002;51:507-516.

    Article  PubMed  CAS  Google Scholar 

  32. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998;396:77-80.

    Article  PubMed  CAS  Google Scholar 

  33. Mitsikostas DD, Knight YE, Lasalandra M, Kavantzas N, Goadsby PJ. Triptans attenuate capsaicin-induced CREB phosphorylation within the trigeminal nucleus caudalis: a mechanism to prevent central sensitization? J Headache Pain 2011;12:411-417.

    Article  PubMed  Google Scholar 

  34. Jahnke A, Johnson JP. Synergistic activation of intercellular adhesion molecule 1 (ICAM-1) by TNF-alpha and IFN-gamma is mediated by p65/p50 and p65/c-Rel and interferon-responsive factor Stat1 alpha (p91) that can be activated by both IFN-gamma and IFN-alpha. FEBS Lett 1994;354:220-226.

    Article  PubMed  CAS  Google Scholar 

  35. Ohmori Y, Schreiber RD, Hamilton TA. Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappaB. J Biol Chem 1997;272:14899-14907.

    Article  PubMed  CAS  Google Scholar 

  36. Pine R. Convergence of TNFalpha and IFNgamma signalling pathways through synergistic induction of IRF-1/ISGF-2 is mediated by a composite GAS/kappaB promoter element. Nucleic Acids Res 1997;25:4346-4354.

    Article  PubMed  CAS  Google Scholar 

  37. Hiroi M, Ohmori Y. The transcriptional coactivator CREB-binding protein cooperates with STAT1 and NF-κB for synergistic transcriptional activation of the CXC Ligand 9/monokine induced by Inteferon γ gene. J Biol Chem 2003;1:651-660.

    Google Scholar 

  38. Tassorelli C, Greco R, Cappelletti D, Sandrini G, Nappi G. Comparative analysis of the neuronal activation and cardiovascular effects of nitroglycerin, sodium nitroprusside and L-arginine. Brain Res 2005;1051:17-24.

    Article  PubMed  CAS  Google Scholar 

  39. Van der Schueren BJ, Lunnon MW, Laurijssens BE, et al. Does the unfavorable pharmacokinetic and pharmacodynamics profile of the iNOS inhibitor GW273629 lead to inefficacy in acute migraine? J Clin Pharmacol 2009;49:281-290.

    Article  PubMed  Google Scholar 

  40. Hoivik HO, Laurijssens BE, Harnisch LO, et al. Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. Cephalalgia 2010;30:1458–1467.

    Article  PubMed  Google Scholar 

  41. Tassorelli C, Joseph SA, Buzzi MG, Nappi G. The effects on the central nervous system of nitroglycerin — putative mechanisms and mediators. Prog Neurobiol 1999;57:607-624.

    Article  PubMed  CAS  Google Scholar 

  42. Greco R, Tassorelli C, Armentero MC, Sandrini G, Nappi G, Blandini F. Role of central dopaminergic circuitry in pain processing and nitriglycerin-induced hyperalgesia. Brain Res 2008;1238:215-223.

    Article  PubMed  CAS  Google Scholar 

Download references

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nicoletta Galeotti.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 510 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Galeotti, N., Ghelardini, C. Inhibition of the PKCγ-ε Pathway Relieves from Meningeal Nociception in an Animal Model: An Innovative Perspective for Migraine Therapy?. Neurotherapeutics 10, 329–339 (2013). https://doi.org/10.1007/s13311-012-0151-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13311-012-0151-8

Keywords

Navigation