Neurochemical Journal

, Volume 7, Issue 4, pp 256–265 | Cite as

The role of noradrenalin in the pathogenesis of primary headaches

  • A. Y. SokolovEmail author
  • O. A. Lyubashina
  • A. V. Amelin
  • S. S. Panteleev
Review Articles


This review is focused on the role of noradrenalin and its receptors in the pathogenesis of primary headaches, in particular, migraine headaches. The data are summarized on the involvement of different adrenoreceptors in the regulation of tone of cerebral vessels and modulation of transmission of nociceptive information in the trigeminovascular system and at the supraspinal level of the CNS. We discuss the pharmacodynamics of several adrenergic drugs that are used for prophylactic treatment of migraine headaches.


noradrenalin adrenoceptors headache migraine trigeminal nerve endogenous antinociceptive system 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Olesen, J., Cephalagia, 2004, vol. 24, pp. 1–160.Google Scholar
  2. 2.
    Sokolov, A.Yu. and Ignatov, Yu.D., Med. Akad. zhurn, 2010, vol. 10, no. 2, pp. 17–31.Google Scholar
  3. 3.
    Cokolov, A.Yu. and Ignatov, Yu.D., Obzory po klin. farm. i lek. ter, 2010, no. 2, pp. 13–26.Google Scholar
  4. 4.
    Amelin, A.V., Ignatov, Yu.D., Skoromets, A.A., and Sokolov, A.Yu., Migren’. Patogenez, klinika, farmakoterapiya: rukovodstvo dlya vrachei (Migraine. Pathogenesis, clinics, pharmacotherapy: manual for physicians), Moscow: MEDpress-inform, 2011.Google Scholar
  5. 5.
    Andreeva, N.G., Strukturno-funktsional’naya organizatsiya nervnoi sistemy (Structure-functional organization of nervous system), St. Petersburg: Izdatel’stvo SPbGU, 2005.Google Scholar
  6. 6.
    Pertovaara, A., Progress in Neurobiology, 2006, vol. 80, pp. 53–83.PubMedGoogle Scholar
  7. 7.
    Bannister, K., Bee, L.A., and Dickenson, A.H., Neurother, 2009, vol. 6, pp. 703–712.Google Scholar
  8. 8.
    Civantos Calzada, B. and Aleixandre de Artiano, A., Pharmacol. Res., 2001, vol. 44, pp. 195–208.PubMedGoogle Scholar
  9. 9.
    Alexander, S.P.H., Mathie, A., and Peters, J.A., Br. J. Pharmacol, 2009, vol. 158, pp. 1–254.Google Scholar
  10. 10.
    Volchkov, V.A., Ignatov, Yu.D., and Strashnov, V.I., Bolevye sindromy v anesteziologii i reanimatologii (Pain syndromes in anaesthesiology and reanimatology), Moscow: MEDpress-inform, 2006.Google Scholar
  11. 11.
    D’Andrea, G., Perini, F., Terrazzino, S., and Nordera, G.P., Neurol. Sci, 2004, vol. 25, pp. 89–92.Google Scholar
  12. 12.
    Castillo, J., Martinez, F., Leira, R., Lema, M., and Noya, M., Headache, 1994, vol. 34, pp. 531–535.PubMedGoogle Scholar
  13. 13.
    Yerdelen, D., Acil, T., Goksel, B., and Karataş, M., Acta Neurol. Belg., 2007, vol. 107, pp. 108–111.PubMedGoogle Scholar
  14. 14.
    D’Andrea, G., Perini, F., Granella, F., Cananzi, A., and Sergi, A., Cephalalgia, 1995, vol. 15, pp. 430–433.PubMedGoogle Scholar
  15. 15.
    Strittmatter, M., Hamann, G.F., Blaes, F., Grauer, M., Fischer, C., and Hoffmann, K.H., Schweiz Med. Wochenschr., 1996, vol. 126, pp. 1054–1061.PubMedGoogle Scholar
  16. 16.
    Leroux, E. and Ducros, A., Orph. J. Rare Dis., 2008, vol. 3, pp. 20–31.Google Scholar
  17. 17.
    Leone, M. and Bussone, G., Lancet Neurol., 2009, vol. 8, pp. 755–64.PubMedGoogle Scholar
  18. 18.
    Strittmatter, M., Grauer, M., Isenberg, E., Hamann, G., Fischer, C., Hoffmann, K.H., Blaes, F., and Schimrigk, K., Headache, 1997, vol. 37, pp. 211–216.PubMedGoogle Scholar
  19. 19.
    Araki, N., Rinsho Shinkeigaku, 1995, vol. 35, pp. 1336–1338.PubMedGoogle Scholar
  20. 20.
    Martínez, F., Castillo, J., Pardo, J., Lema, M., and Noya, M., J. Neurol. Neurosurg. Psychiatry, 1993, vol. 56, pp. 1119–1121.PubMedGoogle Scholar
  21. 21.
    Leistad, R.B., Stovner, L.J., White, L.R., Nilsen, K.B., Westgaard, R.H., and Sand, T., J. Headache Pain, 2007, vol. 8, pp. 157–166.PubMedGoogle Scholar
  22. 22.
    Peroutka, S.J., Headache, 2004, vol. 44, pp. 53–64.PubMedGoogle Scholar
  23. 23.
    Meyer, E.L., Waldenlind, E., and Marcus, C., Cephalalgia, 2006, vol. 26, pp. 831–836.PubMedGoogle Scholar
  24. 24.
    Richter, F., Mikulik, O., Ebersberger, A., and Schaible, H.G., J. Cereb. Blood Flow Met., 2005, vol. 25, pp. 1225–1235.Google Scholar
  25. 25.
    Chiba, S., Nippon Yakur. Zasshi, 2001, vol. 117, pp. 187–194.Google Scholar
  26. 26.
    Edvinsson, L. and Krause, D., Cerebral blood flow and metabolism, Philadelphia: Lippincott, Williams and Wilkins, 2002.Google Scholar
  27. 27.
    Edvinsson, L. and Uddman, R., Brain Res., 2005, vol. 48, pp. 438–456.Google Scholar
  28. 28.
    Wier, W.G., Zang, W.J., Lamont, C., and Raina, H., Exp. Physiol., 2009, vol. 94, pp. 31–37.PubMedGoogle Scholar
  29. 29.
    Mehrotra, S., Gupta, S., Centurión, D., Villalón, C.M., Saxena, P.R., and Vandenbrink, A.M., Basic Clin. Pharmacol. Toxicol., 2007, vol. 100, pp. 279–285.PubMedGoogle Scholar
  30. 30.
    Mehrotra, S., Gupta, S., Garrelds, I.M., Villalón, C.M., Saxena, P.R., Bogers, A.J., and Maassenvandenbrink, A., Naunyn Schmiedebergs Arch. Pharmacol., 2006, vol. 374, pp. 163–175.PubMedGoogle Scholar
  31. 31.
    Tvedskov, J.F., Thomsen, L.L., Thomsen, L.L., Iversen, H.K., Williams, P., Gibson, A., Jenkins, K., Peck, R., and Olesen, J., Cephalalgia, 2004, vol. 24, pp. 1076–1087.PubMedGoogle Scholar
  32. 32.
    Reynier-Rebuffel, A.M., Callebert, J., Launay, J.M., Seylaz, J., and Aubineau, P., Am. J. Physiol., 1997, vol. 273, pp. 845–850.Google Scholar
  33. 33.
    Hargreaves, K.M., Bowles, W.R., and Jackson, D.L., J. Dent. Res., 2003, vol. 82, pp. 398–401.PubMedGoogle Scholar
  34. 34.
    Ivanov, V.E., Neirofiziologicheskie i neirokhimicheskie mekhanizmy deistviya serotoninergicheskikh i adrenergicheskikh sredstv pri eksperimental’noi golovnoi boli, Cand. Sci. (Med) Dissertation, St. Petersburg: SPbGMU im. akad. I. P. Pavlova, 1998.Google Scholar
  35. 35.
    Amelin, A.V., Ignatov, Yu.D., and Skoromets, A.A., Migren’-patogenez, klinika i lechenie (Migraine, pathogenesis, clinics, and treatment), St. Petersburg: SPb meditsinskoe izdatel’stvo, 2001.Google Scholar
  36. 36.
    Markowitz, S., Saito, K., and Moskowitz, M.A., Cephalalgia, 1988, vol. 8, pp. 83–91.PubMedGoogle Scholar
  37. 37.
    Akerman, S., Williamson, D.J., Hill, R.G., and Goadsby, P.J., Eur. J. Pharmacol., 2001, vol. 424, pp. 53–58.PubMedGoogle Scholar
  38. 38.
    Burstein, R. and Jakubowski, M., J. Comp. Neurol., 2005, vol. 493, pp. 9–14.PubMedGoogle Scholar
  39. 39.
    Lindholt, M., Petersen, K.A., and Tvedskov, J.F., Cephalalgia, 2009, vol. 29, pp. 384–387.PubMedGoogle Scholar
  40. 40.
    Bergerot, A., Reynier-Rebuffel, A.M., Callebert, J., and Aubineau, P., Neurosci., 2000, vol. 96, pp. 205–213.Google Scholar
  41. 41.
    Theoharides, T.C., Donelan, J., Kandere-Grzybowska, K., and Konstantinidou, A., Brain Res. Rev., 2005, vol. 49, pp. 65–76.PubMedGoogle Scholar
  42. 42.
    Levy, D., Burstein, R., Kainz, V., Jakubowski, M., and Strassman, A.M., Pain, 2007, vol. 130, pp. 166–176.PubMedGoogle Scholar
  43. 43.
    Zhang, X.C., Strassman, A.M., Burstein, R., and Levy, D., J. Pharmacol. Exp. Ther., 2007, vol. 322, pp. 806–812.PubMedGoogle Scholar
  44. 44.
    Albertyn, J., Barry, R., and Odendaal, C.L., Headache, 2004, vol. 44, pp. 183–185.PubMedGoogle Scholar
  45. 45.
    Messlinger, K., Exp. Brain Res., 2009, vol. 196, pp. 179–193.PubMedGoogle Scholar
  46. 46.
    Strassman, A.M. and Levy, D., J. Neurophysiol., 2006, vol. 95, pp. 1298–1306.PubMedGoogle Scholar
  47. 47.
    Baik, E., Chung, J.M., and Chung, K., J. Pain, 2003, vol. 4, pp. 212–221.PubMedGoogle Scholar
  48. 48.
    Banik, R.K., Sato, J., Giron, R., Yajima, H., and Mizumura, K., Neurosci. Res., 2004, vol. 49, pp. 421–425.PubMedGoogle Scholar
  49. 49.
    Ren, Y., Zou, X., Fang, L., and Lin, Q., J. Neurophysiol., 2005, vol. 93, pp. 365–377.PubMedGoogle Scholar
  50. 50.
    Binder, W., Mousa, S.A., Sitte, N., Kaiser, M., Stein, C., and Schafer, M., Eur. J. Neurosci., 2004, vol. 20, pp. 92–100.PubMedGoogle Scholar
  51. 51.
    Sokolov, A.Yu., Lyubashina, O.A., Ignatov, Yu.D., Amelin, A.V., and Panteleev, S.S., Med. Akad. Zhurn., 2011, vol. 11, no. 2, pp. 3–14.Google Scholar
  52. 52.
    Baron, R., Clin. J. Pain, 2000, vol. 16, pp. 12–20.Google Scholar
  53. 53.
    Honma, Y., Yamakage, M., and Ninomiya, T., Brain Res., 1999, vol. 832, pp. 195–206.PubMedGoogle Scholar
  54. 54.
    Xing, J.L., Hu, S.J., Jian, Z., and Duan, J.H., Pain, 2003, vol. 105, pp. 177–183.PubMedGoogle Scholar
  55. 55.
    Maruo, K., Yamamoto, H., Yamamoto, S., Nagata, T., Fujikawa, H., Kanno, T., Yaguchi, T., Maruo, S., Yoshiya, S., and Nishizaki, T., Pain, 2006, vol. 120, pp. 106–112.PubMedGoogle Scholar
  56. 56.
    Ebersberger, A., Takac, H., Richter, F., and Schaible, H.G., Cephalalgia, 2006, vol. 26, pp. 282–289.PubMedGoogle Scholar
  57. 57.
    Romero-Sandoval, A., McCall, C., and Eisenach, J.C., J. Neurosci., 2005, vol. 25, pp. 8988–8994.PubMedGoogle Scholar
  58. 58.
    Romero-Sandoval, A. and Eisenach, J.C., Anesthesiology, 2006, vol. 104, pp. 351–355.PubMedGoogle Scholar
  59. 59.
    Schurks, M. and Diener, H.C., Eur. J. Neurol., 2008, vol. 15, pp. 1279–1285.PubMedGoogle Scholar
  60. 60.
    Goadsby, P.J., Chabrit, A.R., Andreou, A.P., and Akerman, S., Neurosci., 2009, vol. 161, pp. 327–341.Google Scholar
  61. 61.
    Chiang, C.Y., Hu, J.W., and Sessle, B.J., J. Neurophysiol., 1994, vol. 71, pp. 2430–2445.PubMedGoogle Scholar
  62. 62.
    Stone, L.S., Broberger, C., Vulchanova, L., Wilcox, G.L., Hokfelt, T., Riedl, M.S., and Elde, R., J. Neurosci., 1998, vol. 18, pp. 5928–5937.PubMedGoogle Scholar
  63. 63.
    Pan, Y.Z., Li, D.P., and Pan, H.L., J. Neurophysiol., 2002, vol. 87, pp. 1938–1947.PubMedGoogle Scholar
  64. 64.
    Kawasaki, Y., Kumamoto, E., Furue, H., and Yoshimura, M., Anesthesiology, 2003, vol. 98, pp. 682–689.PubMedGoogle Scholar
  65. 65.
    Mansikka, H., Lahdesmaki, J., Scheinin, M., and Pertovaara, A., Anesthesiology, 2004, vol. 101, pp. 185–190.PubMedGoogle Scholar
  66. 66.
    Li, X. and Eisenach, J.C., J. Pharmacol. Exp. Ther., 2001, vol. 299, pp. 939–944.PubMedGoogle Scholar
  67. 67.
    Olave, M.J. and Maxwell, D.J., J. Neurosci., 2003, vol. 23, pp. 6837–6846.PubMedGoogle Scholar
  68. 68.
    Fairbanks, C.A., Stone, L.S., Kitto, K.F., Nguyen, H.O., Posthumus, I.J., and Wilcox, G.L., J. Pharmacol. Exp. Ther., 2002, vol. 300, pp. 282–290.PubMedGoogle Scholar
  69. 69.
    Wang, X.M., Zhang, Z.J., Bains, R., and Mokha, S.S., Pain, 2002, vol. 98, pp. 27–35.PubMedGoogle Scholar
  70. 70.
    Sonohanata, M., Furue, H., Katafuchi, T., Yasaka, T., Doi, A., Kumamoto, E., and Yoshimura, M., J. Physiol., 2004, vol. 555, pp. 515–526.Google Scholar
  71. 71.
    Baba, H., Shimoji, K., and Yoshimura, M., Anesthesiology, 2000, vol. 92, pp. 473–484.PubMedGoogle Scholar
  72. 72.
    Baba, H., Goldstein, P.A., Okamoto, M., Kohno, T., Ataka, T., Yoshimura, M., and Shimoji, K., Anesthesiology, 2000, vol. 92, pp. 485–492.PubMedGoogle Scholar
  73. 73.
    Harasawa, I., Honda, K., Tanoue, A., Shinoura, H., Ishida, Y., Okamura, H., Murao, N., Tsujimoto, G., Higa, K., Kamiya, H.O., and Takano, Y., Neuroreport, 2003, vol. 14, pp. 1857–1860.PubMedGoogle Scholar
  74. 74.
    Mizukami, T., Kurume Med. J., 2004, vol. 51, pp. 175–183.PubMedGoogle Scholar
  75. 75.
    Sasa, M., Ohno, Y., Ito, J., Kashii, S., Utsumi, S., and Takaori, S., Brain Res., 1986, vol. 377, pp. 337–343.PubMedGoogle Scholar
  76. 76.
    Shields, K.G. and Goadsby, P.J., Brain, 2005, vol. 128, pp. 86–97.PubMedGoogle Scholar
  77. 77.
    Cooper, J.R., Bloom, F.E., and Roth, H.R., The biochemical basis of neuropharmacology, Oxford: Oxford University Press, 2003.Google Scholar
  78. 78.
    Voisin, D.L., Guy, N., Chalus, M., and Dallel, R., J. Physiol., 2005, vol. 566, pp. 929–937.PubMedGoogle Scholar
  79. 79.
    Zhang, C., Yang, S.W., Guo, Y.G., Qiao, J.T., and Dafny, N., Brain Res. Bull., 1997, vol. 42, pp. 273–278.PubMedGoogle Scholar
  80. 80.
    Liu, Y., Broman, J., Zhang, M., and Edvinsson, L., Cephalalgia, 2009, vol. 29, pp. 935–948.PubMedGoogle Scholar
  81. 81.
    Welch, K.M., Nagesh, V., Aurora, S.K., and Gelman, N., Headache, 2001, vol. 41, pp. 629–637.PubMedGoogle Scholar
  82. 82.
    Bajic, D. and Proudfit, H.K., J. Comp. Neurol., 1999, vol. 405, pp. 359–379.PubMedGoogle Scholar
  83. 83.
    Bajic, D., Van Bockstaele, E.J., and Proudfit, H.K., Neurosci., 2001, vol. 104, pp. 181–197.Google Scholar
  84. 84.
    Morgan, M.M., Whittier, K.L., Hegarty, D.M., and Aicher, S.A., Pain, 2008, vol. 140, pp. 376–386.PubMedGoogle Scholar
  85. 85.
    Kincaid, W., Neubert, M.J., Xu, M., Kim, C.J., and Heinricher, M.M., J. Neurophysiol., 2006, vol. 95, pp. 33–41.PubMedGoogle Scholar
  86. 86.
    Carlson, J.D., Maire, J.J., Martenson, M.E., and Heinricher, M.M., J. Neurosci., 2007, vol. 27, pp. 13222–13231.PubMedGoogle Scholar
  87. 87.
    Holmberg, M., Fagerholm, V., and Scheinin, M., Neurosci., 2003, vol. 117, pp. 875–898.Google Scholar
  88. 88.
    Heinricher, M.M., Haws, C.M., and Fields, H.L., in Opposing actions of norepinephrine and clonidine on single pain-modulating neurons in rostral ventromedial medulla, Dubner, R., Gebhart, G.F., and Bond, M.R, Eds.Google Scholar
  89. 89.
    Meng, X.W., Budra, B., Skinner, K., Ohara, P.T., and Fields, H.L., J. Comp. Neurol., 1997, vol. 377, pp. 381–391.PubMedGoogle Scholar
  90. 90.
    Bie, B., Fields, H.L., Williams, J.T., and Pan, Z.Z., J. Neurosci., 2003, vol. 23, pp. 7950–7957.PubMedGoogle Scholar
  91. 91.
    Nuseir, K., Heidenreich, B.A., and Proudfit, H.K., Brain Res., 1999, vol. 822, pp. 1–7.PubMedGoogle Scholar
  92. 92.
    Holden, J.E. and Naleway, E., Brain Res., 2001, vol. 911, pp. 27–36.PubMedGoogle Scholar
  93. 93.
    Holden, J.E., Van Poppel, A.Y., and Thomas, S., Brain Res., 2002, vol. 953, pp. 195–204.PubMedGoogle Scholar
  94. 94.
    Silberstein, S.D., Rev. Neurol. D, vol. 2, no. is. 2005, pp. 167–175.Google Scholar
  95. 95.
    Pascual, J., Rivas, M.T., and Leira, R., Acta Neurol. Scand., 2007, vol. 115, pp. 81–83.PubMedGoogle Scholar
  96. 96.
    Saper, J.R., Winner, P.K., and Lake, A.E., Headache, 2001, vol. 41, pp. 357–368.PubMedGoogle Scholar
  97. 97.
    Saper, J.R., Lake, A.E., Cantrell, D.T., Winner, P.K., and White, J.R., Headache, 2002, vol. 42, pp. 470–482.PubMedGoogle Scholar
  98. 98.
    Freitag, F.G., CNS Drugs, 2003, vol. 17, pp. 373–381.PubMedGoogle Scholar
  99. 99.
    Koch, H.J. and Jürgens, T.P., Drugs, 2009, vol. 69, pp. 1–19.PubMedGoogle Scholar
  100. 100.
    Smitherman, T.A., Walters, A.B., Maizels, M., and Penzien, D.B, CNS Neurosci. Ther., 2011, vol. 17, pp. 462–469.PubMedGoogle Scholar
  101. 101.
    Dharmshaktu, P., Tayal, V., and Kalra, B.S., J. Clin. Pharmacol., 2012, vol. 52, pp. 6–17.PubMedGoogle Scholar
  102. 102.
    Leo, R.J. and Brooks, V.L., Curr. Opin. Investig. Drugs, 2006, vol. 7, pp. 637–642.PubMedGoogle Scholar
  103. 103.
    Nakajima, K., Obata, H., Iriuchijima, N., and Saito, S., Pain, 2012, vol. 153, pp. 990–997.PubMedGoogle Scholar
  104. 104.
    Torrente Castells, E., Vázquez Delgado, E., and Gay Escoda, C., Med. Oral. Patol. Oral. Cir. Bucal, 2008, vol. 13, pp. 567–572.Google Scholar
  105. 105.
    Ashina, S., Bendtsen, L., and Jensen, R., Pain, 2004, vol. 108, pp. 108–114.PubMedGoogle Scholar
  106. 106.
    Amelin, A.V., Tarasova, S.V., Ignatov, Yu.D., Skoromets, A.A., and Myatleva, M.I., Zhurn. Nevr. Psikh. Im. S.S.Korsakova, 2007, vol. 107, pp. 38–44.Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2013

Authors and Affiliations

  • A. Y. Sokolov
    • 1
    • 2
    • 4
    Email author
  • O. A. Lyubashina
    • 1
  • A. V. Amelin
    • 3
  • S. S. Panteleev
    • 1
    • 2
  1. 1.Pavlov Institute of PhysiologyRussian Academy of SciencesSt. PetersburgRussia
  2. 2.Valdman Institute of PharmacologyFirst Pavlov State Medical UniversitySt. PetersburgRussia
  3. 3.Department of Neurology and NeurosurgeryFirst Pavlov State Medical UniversitySt. PetersburgRussia
  4. 4.St. PetersburgRussia

Personalised recommendations