Role of tachykinins in non-adrenergic non-cholinergic excitation in smooth muscles of the gastrointestinal tract


Two peptides from the tachykinin family, substance P (SP) and neurokinin A (NKA), were identified as neurotransmitters (co-transmitters) of non-adrenergic non-cholinergic (NANCh) excitation in the gastrointestinal tract. The contraction of smooth muscles produced by tachykinins released from the excitatory enteric motoneurons is mediated by the NK1 and/or the NK2 tachykinin receptors. The differing contribution of these receptors in mediating the NANCh excitatory responses has been demonstrated in various regions of the intestine. The NK3 tachykinin receptors are confined only to the enteric neurons; they mediate release of different excitatory and inhibitory transmitters. The main secondary messenger pathway for all three tachykinin receptors is phosphoinositide breakdown that results in an increase of intracellular Ca2+ concentration. Signal transduction mechanisms are still not adequately known for tahykinin receptors. A multiple ionic mechanism has been proposed to mediate excitatory action of SP; it comprises activation of non-selective cationic channels, or activation of maxi Cl channels, and/or inhibition of K+ channels. Data about the ionic mechanism underlying the NK2 receptor activation are still missing. In conclusion, SP and NKA play a physiological role as NANCh neurotransmitters in smooth muscles of the gastrointestinal tract and, therefore, tachykinins may have a significant pathophysiological relevance in humans.

This is a preview of subscription content, access via your institution.


  1. 1.

    U. S. Von Euler and J. H. Gaddum, “An unidentified depressor substance in certain tissue extracts,”J. Physiol.,72, 74–87 (1931).

    Google Scholar 

  2. 2.

    M. M. Chang, S. E. Leeman, and H. D. Niall, “Amino acid sequence of substance P,”Nature,232, 86–87 (1971).

    Google Scholar 

  3. 3.

    J. E. Maggio, “Tachykinins,”Annu. Rev. Neurosci.,11, 13–21 (1988).

    Google Scholar 

  4. 4.

    S. Nakanishi, “Mammalian tachykinin receptors,”Annu. Res. Neurosci.,14, 123–136 (1991).

    Google Scholar 

  5. 5.

    H. Nawa, H. Kotani, and S. Nakanishi, “Tissue-specific generation of two preprotachykinin mRNAs from one gene by alternative RNA aplicing,”Nature,312, 729–734 (1984).

    Google Scholar 

  6. 6.

    T. Bonner, H. U. Afflolter, A. C. Young, and W. S. Young, “AcDNA encoding the precursor of the rat neuropeptide neurokinin B,”Mol. Brain Res.,2, 243–249 (1987).

    Google Scholar 

  7. 7.

    C. A. Maggi, R. Patacchini, P. Rovero, and A. Gichetti, “Tachykinin receptors and tachykinin receptor antagonists,”J. Auton. Pharmacol.,13, 23–93 (1993).

    Google Scholar 

  8. 8.

    M. Schultzberg, T. Hokfelt, G. Nilsson, et al., “Distribution of peptide and catecholamine neurons in the gastrointestinal tract of rat and guinea-pig: immunohistochemical studies with antisera to substance P, VIP, enkephalins, somatostatin, gastrin, neurotensin and dopamine-b-hydroxylase,”Neuroscience,5, 689–744 (1980).

    Google Scholar 

  9. 9.

    J. B. Furness and M. Costa,The Enteric Nervous System, Churchill Livingstone (1987).

  10. 10.

    M. Costa, J. B. Furness, and I. J. Llewellyn-Smith, “Histochemistry of the enteric nervous system,” in:Physiology of the Gastro-Intestinal Tract, L. R. Johnson (ed.), Raven Press, New York (1987), pp. 1–4.

    Google Scholar 

  11. 11.

    S. J. H. Brookes, P. A. Steele, and M. Costa, “Identification and immunohistochemistry of cholinergic and non-cholinergic circular muscle motor neurons in the guinea-pig small intestine,”Neuroscience,42, 863–878 (1991).

    Google Scholar 

  12. 12.

    P. Schmidt, S. S. Pouson, T. N. Rasmussen, et al., “Substance P and neurokinin A are co-distributed and co-localized in the porcine gasrointestinal tract,”Peptides,12, 964–973 (1991).

    Google Scholar 

  13. 13.

    C. W. R. Shuttleworth, R. Murphy, J. B. Furness, and S. Pompolo, “Comparison of the presence and actions of substance P and neurokinin A in guinea-pigtaenia coli,”Neuropeptides,19, 23–34 (1991).

    Google Scholar 

  14. 14.

    H. P. Too, J. L. Cordova, and J. E. Maggio, “A novel radioimmunoassay for neuromedin K. I. Absence of neuromedin K-like immunoreactivity in guinea-pig ileum and urinary bladder. II. Heterogeneity of tachykinins in guinea-pig tissues,”Regulat. Peptides,26, 93–105 (1989).

    Google Scholar 

  15. 15.

    K. Tateishi, S. Kishimoto, H. Kobayashi, et al., “Distribution and localization of neurokinin A-like immunoreactivity and neurokinin B-like immunoreactivity in rat peripheral tissue,”Regulat. Peptides,30, 193–200 (1990).

    Google Scholar 

  16. 16.

    Y. Yokota, Y. Sasai, K. Tanaka, et al., “Molecular characterization of a functional cDNA for rat substance P receptor,”J. Biol. Chem.,264, 17469–17652 (1989).

    Google Scholar 

  17. 17.

    Y. Takeda, K. B. Chou, J. Takeda, et al., “Molecular cloning, structural characterization and functional expression of the human substance P receptor,”Biochem. Biophys. Res. Commun.,179, 1232–1240 (1991).

    Google Scholar 

  18. 18.

    C. A. Maggi, “The mammalian tachykinin receptors,”Gen. Pharmacol.,26, 911–944 (1995).

    Google Scholar 

  19. 19.

    R. M. Kris, V. South, A. Saltzman, et al., “Cloning and expression of the human substance K receptor and analysis of its role in mitogenesis,”Cell Growth Differentiation,2, 15–22 (1991).

    Google Scholar 

  20. 20.

    B. J. Williams, N. R. Curtis, A. T. McKnight, et al., “Development of NK-2 selective antagonists,”Regulat. Peptides,22, 189 (1988).

    Google Scholar 

  21. 21.

    C. A. Maggi, R. Patacchini, S. Giuliani, et al., “Competitive antagonists discriminate between NK-2 tachykinin receptor subtypes,”Br. J. Pharmacol.,100, 588–592 (1990)

    Google Scholar 

  22. 22.

    G. Buell, M. F. Schultz, S. J. Arkinstall, et al., “Molecular characterization, expression and localization of human neurokinin 3 receptor,”FEBS Lett.,299, 90–95 (1992).

    Google Scholar 

  23. 23.

    X. Edmonds-Alt, D. Bichon, J. P. Ducoux, et al., “SR 142,801, the first potent nonpeptide antagonist of the tachykinin NK3 receptor,”Life Sci. Pharmacol. Lett.,56, PL27-PL32 (1995).

    Google Scholar 

  24. 24.

    P. Boden, J. M. Eden, J. Hodgson, et al., “The rational development of small molecule tachykinin NK3 receptor selective antagonist — the utilization of a dipeptide chemical library in drug design,”Bioorg. Med. Chem. Lett.,4, 1679–1684 (1994).

    Google Scholar 

  25. 25.

    P. W. Manthyh, T. Gates, C. R. Manthyh, and J. E. Maggio, “Autoradiographic localization and characterization of tachykinin receptor binding sites in the rat brain and peripheral tissues,”J. Neurosci.,9, 258–279 (1989).

    Google Scholar 

  26. 26.

    K. Tsuchida, R. Shigemoto, Y. Yokota, and S. Nakanishi, “Tissue distribution and quantification of the mRNA for three rat tachykinin receptors,”Eur. J. Biochem.,193, 751–757 (1990).

    Google Scholar 

  27. 27.

    E. F. Grady, P. Baluk, H. Wong, et al., “Localization of NK-1, NK-2 and NK-3 receptors by immunofluorescence and confocal microscopy,”in: Tachykinins' 95, Abstr., Florence, Italy (1995), p. 208.

  28. 28.

    C. A. Maggi, R. Patacchini, A. Giachetti, and A. Meli, “Tachykinin receptors in the circular muscle of the guinea-pig ileum,”Br. J. Pharmacol.,101, 996–1000 (1990).

    Google Scholar 

  29. 29.

    V. P. Zagorodnyuk, P. Santicioli, and C. A. Maggi, “Different calcium influx pathways mediate tachykinin contraction in the circular muscle of guinea-pig colon,”Eur. J. Pharmacol.,255, 9–15 (1994).

    Google Scholar 

  30. 30.

    A. D. Sandler, J. W. Maher, J. V. Weinstick, et al., “Tachykinins in the canine gastroesophageal junction,”Am. J. Surg.,161, 165–170 (1991).

    Google Scholar 

  31. 31.

    O. Huber, C. Bertrand, N. W. Bunnett, et al., “Tachykinins mediate contraction of the human lower esophageal sphincterin vitro via acivation of NK2 receptors,”Eur. J. Pharmacol.,239, 103–109 (1993).

    Google Scholar 

  32. 32.

    V. P. Zagorodnyuk and C. A. Maggi, “Neuronal tachykinin NK2 receptors mediate release of non-adrenergic non-cholinergic inhibitory transmitters in the circular muscle of guinea-pig colon,”Neuroscience,69, 644–650 (1995).

    Google Scholar 

  33. 33.

    C. A. Maggi, V. P. Zagorodnyuk, and S. Giuliani, “Tachykinin NK3 receptor mediates NANC hyperpolarization and relaxation via nitrix oxide release in the circular muscle of the guinea-pig colon,”Regulat. Peptides,53, 259–274 (1994).

    Google Scholar 

  34. 34.

    L. Bartho and P. Holzer, “Search for a physiological role of substance P in gastrointestinal motility,”Neuroscience,16, 1–32 (1985).

    Google Scholar 

  35. 35.

    V. Bauer and H. Kuriyama, “The nature of non-cholinergic non-adrenergic transmission in longitudinal and circular muscle of the guinea-pig ileum,”J. Physiol.,330, 375–391 (1982).

    Google Scholar 

  36. 36.

    J. P. Niel, R. A. R. Bywater, and G. S. Taylor, “Effect of substance P on non-cholinergic fast and slow post-stimulus depolarization in the guinea-pig ileum,”J. Auton. Nerv. Syst.,9, 573–584 (1983).

    Google Scholar 

  37. 37.

    R. A. R. Bywater and G. S. Taylor, “Noncholinergic excitatory and inhibitory junction potentials in the circular smooth muscle of the guinea-pig ileum,”J. Physiol.,374, 153–164 (1986).

    Google Scholar 

  38. 38.

    J. R. Crist, X. D. He, and R. K. Goyal, “The nature of non-cholinergic membrane potential responses to transmural stimulation in guinea-pig ileum,”Gastroenterology,100, 1006–1015 (1991).

    Google Scholar 

  39. 39.

    V. P. Zagorodnyuk, P. Santicioli, C. A. Maggi, and A. Gichetti, “Evidence that tachykinin NK1 and NK2 receptors mediate non-adrenergic non-cholinergic excitation and contraction in the circular muscle of guinea-pig duodenum,”Br. J. Pharmacol.,115, 237–246 (1995).

    Google Scholar 

  40. 40.

    I. A. Vladimirova and M. F. Shuba, “Synaptic processes in smooth muscles,”Neirofiziologiya,16, 307–319 (1984).

    Google Scholar 

  41. 41.

    V. P. Zagorodnyuk, P. Santicioli, and C. A. Maggi, “Tachykinin NK1 but not NK2 receptors mediate non-adrenergic non-cholinergic excitatory junction potential in the circular muscle of guinea-pig colon,”Br. J. Pharmacol.,110, 795–803 (1993).

    Google Scholar 

  42. 42.

    C. A. Maggi, V. P. Zagorodnyuk, and S. Giuliani, “Specialization of tachykinin NK1 and NK2 receptors in producing fast and slow atropine-resistant neurotransmission to the circular muscle of the guinea-pig colon,”Neuroscience,63, 1137–1152 (1994).

    Google Scholar 

  43. 43.

    R. A. R. Bywater and G. S. Taylor, “Non-cholinergic fast and slow post-stimulus depolarization in the guinea-pig ileum,”J. Physiol.,340, 47–56 (1983)

    Google Scholar 

  44. 44.

    L. Bartho, P. Santicioli, R. Patacchini, and C. A. Maggi, “Tachykininergic transmission to the circular muscle of the guinea-pig ileum: evidence for involvement of NK-2 receptors,”Br. J. Pharmacol.,105, 805–810 (1992).

    Google Scholar 

  45. 45.

    S. Guard and S. P. Watson, “Tachykinin receptor types: classification and membrane signalling mechanisms,”Neurochemistry,18, 149–165 (1991).

    Google Scholar 

  46. 46.

    Y. Nakajima, K. Tsuchida, M. Negishi, et al., “Direct linkage of three tachykinin receptors to simulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected chinese hamster ovary cells,”J. Biol. Chem.,267, 2437–2442 (1992).

    Google Scholar 

  47. 47.

    M. Mitsuhashi, Y. Ohashi, S. Shichijo, et al., “Multiple intracellular signaling pathways of the substance P receptor,”FASEB J., 6, A1562 (1992).

    Google Scholar 

  48. 48.

    S. Sagan, A. Brunissen, H. Josien, et al., “[Pro9]SP-like and septide-like peptides trigger different pharmacological responses in CHO cells transfected with human NK-1 receptor,” in:Tachykinins' 95, Abstr., Florence, Italy (1995), p. 15.

  49. 49.

    A. W. Mangel and I. L. Taylor, “Modulation of electrical activity in gastrointestinal smooth muscle by peptides,”Regulat. Peptides,42, 1–13 (1992).

    Google Scholar 

  50. 50.

    P. Holzer and I. Th. Lippe, “Substance P can contract the longitudinal muscle of the guinea-pig small intestine by releasing intracellular calcium,”Br. J. Pharmacol.,82, 259–267 (1984).

    Google Scholar 

  51. 51.

    E. A. Mayer, X. P. Sun, S. Supplission, et al., “Neurokinin receptor-mediated regulation of [Ca2+]1 and Ca-sensitive ion channels in mammalian colonic muscle,”Ann. New York Acad. Sci.,632, 439–441 (1991).

    Google Scholar 

  52. 52.

    G. R. Seabrook and T. M. Fong, “Thapsigargine blocks the mobilization of intracellular calcium caused by activation of human NK1 receptors expressed in Chinese hamster ovary cells,”Neurosci. Lett.,152, 9–12 (1993).

    Google Scholar 

  53. 53.

    C. D. Benham and T. B. Bolton, “Comparison of the excitatory actions of substance P, carbachol, histamine and prostaglandin F on the smooth muscle of thetaenia of the guinea-pigcaecum,”Br. J. Pharmacol.,80, 409–420 (1982).

    Google Scholar 

  54. 54.

    C. W. R. Shuttleworth, K. M. Sanders, and K. D. Keff “Inhibition of nitric oxide synthesis reveals non-cholinergic excitatory neurotransmission in the canine proximal colon,”Br. J. Pharmacol.,109, 739–747, (1993).

    Google Scholar 

  55. 55.

    L. H. Clapp, M. B. Vivaudou, J. J. Singer, and J. V. Walsh, Jr., “Substance P, like acetylcholine, augments one type of Ca2+ current in isolated smooth muscle cells,”Pflügers Arch.,413, 565–567 (1989).

    Google Scholar 

  56. 56.

    E. A. Mayer, D. D. Loo, W. J. Snape, Jr., and G. Sachs, “The activation of calcium and calcium-activated potassium channels in mammalian colonic smooth muscle by substance P,”J. Physiol.,420, 47–71 (1990).

    Google Scholar 

  57. 57.

    K. Nakazawa, K. Inoue, K. Fujimori, and A. Tanaka, “Difference between substance P- and acetylcholine-induced currents in mammalian smooth muscle cells,”Eur. J. Pharmacol.,179, 453–456 (1990).

    Google Scholar 

  58. 58.

    H. K. Lee, C. W. R. Shuttleworth, and K. M. Sanders, “Tachykinins activate non-selective cation currents in canine colonic myocytes,”Am. J. Physiol. (1996).

  59. 59.

    D. Regoli, G. Drapeau, S. Dion, and P. D'Orleans-Juste, “Pharmacological receptors for substance P and neurokinins,”Life Sci.,40, 109–117 (1987).

    Google Scholar 

  60. 60.

    K. Fujisawa and Y. Ito, “The effects of substance P on smooth muscle cells and on neuro-effector transmission in the guinea-pig ileum,”Br. J. Pharmacol.,76, 279–290 (1982).

    Google Scholar 

  61. 61.

    P. Holzer and U. Petsche, “On the mechanism of contraction and desensitization by substance P in the intestinal smooth muscle of the guinea-pig,”J. Physiol.,431, 549–568 (1983).

    Google Scholar 

  62. 62.

    S. M. Sims, J. V. Walsh, Jr, and J. J. Singer, “Substance P and acetylcholine both suppress the same K+ current in dissociated smooth muscle cells,”Am. J. Physiol.,251, C580-C587 (1986).

    Google Scholar 

  63. 63.

    E. A. Mayer, D. D. F. Loo, A. Kodner, and S. N. Reddy, “Differential modulation of [Sar9] substance P sulfone-activated K+ channels by substance P,”Am. J. Physiol.,257, G887-G897 (1989).

    Google Scholar 

  64. 64.

    W. P. Sun, S. Supplission, and E. Mayer, “Chloride channels in myocytes from rabbit colon are regulated by a pertussis toxin-sensitive G-protein,”Am. J. Physiol.,264, G774-G785 (1993).

    Google Scholar 

  65. 65.

    L. J. Janssen and S. M. Sims, “Substance P activates Cl and K+ conductances in guinea-pig tracheal smooth muscle cells,”Can. J. Physiol. Pharmacol.,72, 705–710 (1994).

    Google Scholar 

  66. 66.

    P. P. Bertrand and J. J. Galligan, “Contribution of chloride conductance increase to slow EPSC and tachykinin current in guinea-pig myenteric neurones,”J. Physiol.,481.1, 47–60 (1994).

    Google Scholar 

  67. 67.

    K. Nakazawa, K. Inoue, K. Fujimori, and A. Tanaka, “Neurokinin A suppresses a voltage-gated K+ current in smooth muscle from ratvas deferens,”Eur. J. Pharmacol.,182, 189–192 (1990).

    Google Scholar 

Download references

Author information



Additional information

Neirofiziologiya/Neurophysiology, Vol. 27, No. 5/6, pp. 425–432, September–December, 1995.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zagorodnyuk, V.P., Belevich, A.É., Maggi, C.A. et al. Role of tachykinins in non-adrenergic non-cholinergic excitation in smooth muscles of the gastrointestinal tract. Neurophysiology 27, 338–344 (1995).

Download citation


  • Ionic Mechanism
  • Enteric Neuron
  • Signal Transduction Mechanism
  • Secondary Messenger
  • Excitatory Response