Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Gut Tachykinins

John E Maggio, Patrick W Mantyh

10.1002/cphy.cp060227

Source: Supplement 17: Handbook of Physiology, The Gastrointestinal System, Neural and Endocrine Biology

Originally published: 1989

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Discovery and Early Studies of Tachykinins
1.1 Discovery of Substance P
1.2 Discovery of Nonmammalian Tachykinins
1.3 Rediscovery of Substance P
1.4 Caveats for Interpretation of Substance P Research
2 Pharmacology and Physiology of Substance P
2.1 Structure‐Activity Relationships
2.2 Biosynthesis
2.3 Release
2.4 Receptors and Second Messengers
2.5 Spasmogenic Activity
2.6 Conduction of Nociceptive Information
2.7 Hemodynamic Regulation
2.8 Exocrine Effects
2.9 Endocrine Effects
2.10 Pathology
3 Distribution and Location of Tachykinins in the Gastrointestinal Tract
3.1 Caveats
3.2 Location of Fibers and Cells Containing Substance P‐Like Immunoreactivity in the Gastrointestinal Tract
3.3 Location of Substance P Receptors in the Gastrointestinal Tract
3.4 Pancreas
3.5 Salivary Glands
4 Ontogeny and Phylogeny
4.1 Ontogeny
4.2 Phylogeny
5 Recent Developments
5.1 Discovery of Novel Mammalian Tachykinins
5.2 Pharmacology of Substance K and Neuromedin K
5.3 Tissue Distribution of Novel Mammalian Tachykinins
5.4 Characteristics of Binding Sites for Novel Mammalian Tachykinins
6 Mode of Action of Tachykinins
7 Conclusions
8 Addendum
8.1 Nomenclature
8.2 Novel Tachykinins
8.3 Molecular Biology
8.4 Binding and Autoradiography
8.5 Tachykinin Receptor‐Binding Sites in the Canine Gastrointestinal Tract
8.6 Tachykinins, Tachykinin Receptors, and Inflammatory Bowel Disease
Figure 1. Figure 1.

Major structural features of tachykinins. Based on nature of residue X, substance P, physalaemin, Lys5Thr6‐physalaemin, uperolein, hylambatin, enterohylambatin, and substance P‐like peptide are aromatic tachykinins; substance K, neuromedin K, eledoisin, phyllomedusin, kassinin, Glu2Pro5‐kassinin, and enterokassinin are aliphatic tachykinins. ‐NH2 represents a COOH‐terminal α‐carboxamide moiety. Although much more varied than highly conserved carboxy region, amino termini in tachykinins also show some sequence homology.
Figure 2. Figure 2.

Structures of 2 preprotachykinins from bovine striatum. Boxes below structures, location of mature peptide sequences; amino acid numbers are given above. NH2, amidation site (a glycine residue in precursors). Paired basic residues, proteolytic processing sites. Dashed lines, β‐preprotachykinin region deleted from α‐preprotachykinin. Protein structures are derived indirectly from complementary DNAs cloned and sequenced by Nawa et al. 167).

From Nawa et al. 167). Reprinted by permission from Nature, copyright 1983, MacMillan Journals Limited
Figure 3. Figure 3.

Autoradiographic localization of substance P (SP) and substance K (SK) receptor‐binding sites in cardia of canine stomach. Panel a: light‐field photomicrograph of canine cardia stained with hematoxylin and eosin stain (HE); panels b and c: dark‐field photomicrographs of the tritium‐sensitive film that overlaid a for 10 days. Light areas, high concentrations of binding sites of [125I]Bolton‐Hunter conjugates of SP ([125I]BHSP) (b) and SK ([125I]BHSK) (c). Highest concentration of SP‐binding sites (b) is over cells in basal mucosa (Mc), whereas lower levels are present in muscularis mucosa (MM), arterioles (A), submucosa (Sub Mc), and circular muscle (CM). In contrast SK‐binding sites (c) are confined primarily to circular muscle. Control sections were treated identically to sections shown in b and c, except that 1 μM of cold peptide was added to the incubation medium. Unless otherwise noted, control sections were essentially blank. For an example see the NMK binding in Fig. 4A, which showed no specific binding and was essentially identical to control sections for both SP and SK. Bar, 0.80 mm.
Figure 4. Figure 4.

Autoradiographic localization of BHSP‐ and BHSK‐binding sites in canine fundus. High concentration of SP‐binding sites in cells in basal mucosa (Mc), circular muscle (CM), and arterioles (A) and low concentration in muscularis mucosa (MM). In contrast SK‐binding sites are found over the circular muscle and a low concentration over the mucosa. Bar, 1.22 mm.

See Fig. 1A for further explanation
Figure 5. Figure 5.

Autoradiographic localization of BHSP‐ and BHSK‐binding sites in canine pyloric sphincter. Very high concentration of specific BHSK‐binding sites over inner thickening of circular muscle (CM) corresponds to the pyloric sphincter, whereas only a moderate concentration of BHSP‐binding sites are expressed by this muscle. Only BHSK‐binding sites could be detected in outer circular muscle. LM, longitudinal muscle.

See Fig. 1A for further explanation
Figure 6. Figure 6.

Autoradiographic localization of binding sites of BHSP, BHSK, and [125I]BH‐neuromedin K (BHNMK) in canine jejunum. Note high concentration of BHSP‐binding sites in longitudinal muscle (LM), inner circular muscle (iCM), and muscularis mucosa (MM), whereas BHSK sites are localized over muscularis mucosa, inner circular muscle, and myenteric plexus (MP). Panel c: no NMK‐binding sites are present. Absence of NMK‐binding sites was observed for every gastrointestinal segment examined. Mc, mucosa. Bar, 1.75 mm.

See Fig. 1A for further explanation
Figure 7. Figure 7.

Autoradiographic localization of BHSP‐ and BHSK‐binding sites in canine ileum. High concentrations of SP‐binding sites present in muscularis mucosa (MM) and inner circular muscle (iCM). Note that low concentrations of BHSP‐binding sites are present in longitudinal muscle (LM), muscularis mucosa, and epithelium in serosal side of mucosa (Mc). BHSP‐binding sites over arterioles and epithelium are shown in higher power in Fig. 6A. BHSK‐binding sites were detectable only in inner circular muscle. Bar, 1.07 mm.
Figure 8. Figure 8.

BHSP‐binding sites in mucosal epithelium in ileum (a, b) and appendix (c, d). Panels a and c: hematoxylin and eosin‐stained sections of ileum and appendix, respectively; b and d: dark‐field autoradiograms showing distribution of SP‐binding sites. In both ileum and appendix, epithelium on serosal side of mucosa contains a moderate‐to‐heavy concentration of SP‐binding sites. In addition, binding sites can be observed in the muscularis mucosa (MM), inner circular muscle (iCM), and myenteric plexus (MP) in the ileum and the muscularis mucosa and inner circular muscle in the appendix. A, arteriole; Mc, mucosa. Bar, 1.10 mm.
Figure 9. Figure 9.

Localization of BHSP‐ and BHSK‐binding sites in canine colon. Note high concentration of BHSP‐binding sites associated with longitudinal muscle (LM), circular muscle (CM), arterioles (A), muscularis mucosa (MM), base of the mucosa (Muc), and the germinal (g) but not the proliferative (p) layer of lymph nodule (Lym). Bar, 0.95 mm.

See Fig. 1A for further explanation
Figure 10. Figure 10.

that express BHSP receptor‐binding sites. In lymph nodule only lightly stained germinal center (g) is labeled, while the more darkly hematoxylin and eosin‐stained proliferative zone (p) is unlabeled. Binding sites expressed by arterioles include both the smooth muscle and the endothelial cells that border on lumen. CM, circular muscle; MM, muscularis mucosa. Bar, 0.85 mm.

See Fig. 1A for further explanation
Figure 11. Figure 11.

Localization of BHSP‐binding sites in lymph nodules (Lym) that are located in basal mucosa in antrum of dog. As in lymph nodule shown in Fig. 10A, BHSP‐binding sites are associated with lightly stained germinal center rather than more darkly stained proliferative zone. A, arteriole. Bar, 0.75 mm.

See Fig. 1A for further explanation
Figure 12. Figure 12.

Dark‐field autoradiograms showing distribution of binding sites of substance P (SP) in transverse sections of colon obtained from margins of extensive resection for carcinoma (a) and from patients with Crohn's disease (b) and ulcerative colitis (c). Whereas in normal colon (a) a moderate concentration of SP receptor‐binding sites is expressed by external circular muscle (CM) and tunica media of a large artery in the serosa, in colon affected by either Crohn's disease (b) or ulcerative colitis (c), arterioles, venules, and lymph nodules express very high levels of SP receptor‐binding sites. LM, longitudinal muscle. Bar, 1.4 mm.
Figure 13. Figure 13.

Histogram showing changes in location and concentration of SP‐ and SK‐binding sites in surgical specimens of human colon obtained from carcinoma resection (open bars), Crohn's disease (hatched bars), and ulcerative colitis (solid bars). In this histogram, 100% specific binding is that concentration of specific SP‐binding sites expressed by smooth muscle (SM) of normal external circular muscle (CM). Although SP receptor‐binding sites are undetectable in blood vessels (bv) vascularizing the circular and longitudinal muscle (LM) and in lymph nodules of normal patients, in Crohn's and ulcerative colitis patients they reach levels that are the highest observed in the human gastrointestinal tract. Distinct binding sites for neuromedin K were not detected in any area of the human gastrointestinal tract.


Figure 1.

Major structural features of tachykinins. Based on nature of residue X, substance P, physalaemin, Lys5Thr6‐physalaemin, uperolein, hylambatin, enterohylambatin, and substance P‐like peptide are aromatic tachykinins; substance K, neuromedin K, eledoisin, phyllomedusin, kassinin, Glu2Pro5‐kassinin, and enterokassinin are aliphatic tachykinins. ‐NH2 represents a COOH‐terminal α‐carboxamide moiety. Although much more varied than highly conserved carboxy region, amino termini in tachykinins also show some sequence homology.



Figure 2.

Structures of 2 preprotachykinins from bovine striatum. Boxes below structures, location of mature peptide sequences; amino acid numbers are given above. NH2, amidation site (a glycine residue in precursors). Paired basic residues, proteolytic processing sites. Dashed lines, β‐preprotachykinin region deleted from α‐preprotachykinin. Protein structures are derived indirectly from complementary DNAs cloned and sequenced by Nawa et al. 167).

From Nawa et al. 167). Reprinted by permission from Nature, copyright 1983, MacMillan Journals Limited


Figure 3.

Autoradiographic localization of substance P (SP) and substance K (SK) receptor‐binding sites in cardia of canine stomach. Panel a: light‐field photomicrograph of canine cardia stained with hematoxylin and eosin stain (HE); panels b and c: dark‐field photomicrographs of the tritium‐sensitive film that overlaid a for 10 days. Light areas, high concentrations of binding sites of [125I]Bolton‐Hunter conjugates of SP ([125I]BHSP) (b) and SK ([125I]BHSK) (c). Highest concentration of SP‐binding sites (b) is over cells in basal mucosa (Mc), whereas lower levels are present in muscularis mucosa (MM), arterioles (A), submucosa (Sub Mc), and circular muscle (CM). In contrast SK‐binding sites (c) are confined primarily to circular muscle. Control sections were treated identically to sections shown in b and c, except that 1 μM of cold peptide was added to the incubation medium. Unless otherwise noted, control sections were essentially blank. For an example see the NMK binding in Fig. 4A, which showed no specific binding and was essentially identical to control sections for both SP and SK. Bar, 0.80 mm.



Figure 4.

Autoradiographic localization of BHSP‐ and BHSK‐binding sites in canine fundus. High concentration of SP‐binding sites in cells in basal mucosa (Mc), circular muscle (CM), and arterioles (A) and low concentration in muscularis mucosa (MM). In contrast SK‐binding sites are found over the circular muscle and a low concentration over the mucosa. Bar, 1.22 mm.

See Fig. 1A for further explanation


Figure 5.

Autoradiographic localization of BHSP‐ and BHSK‐binding sites in canine pyloric sphincter. Very high concentration of specific BHSK‐binding sites over inner thickening of circular muscle (CM) corresponds to the pyloric sphincter, whereas only a moderate concentration of BHSP‐binding sites are expressed by this muscle. Only BHSK‐binding sites could be detected in outer circular muscle. LM, longitudinal muscle.

See Fig. 1A for further explanation


Figure 6.

Autoradiographic localization of binding sites of BHSP, BHSK, and [125I]BH‐neuromedin K (BHNMK) in canine jejunum. Note high concentration of BHSP‐binding sites in longitudinal muscle (LM), inner circular muscle (iCM), and muscularis mucosa (MM), whereas BHSK sites are localized over muscularis mucosa, inner circular muscle, and myenteric plexus (MP). Panel c: no NMK‐binding sites are present. Absence of NMK‐binding sites was observed for every gastrointestinal segment examined. Mc, mucosa. Bar, 1.75 mm.

See Fig. 1A for further explanation


Figure 7.

Autoradiographic localization of BHSP‐ and BHSK‐binding sites in canine ileum. High concentrations of SP‐binding sites present in muscularis mucosa (MM) and inner circular muscle (iCM). Note that low concentrations of BHSP‐binding sites are present in longitudinal muscle (LM), muscularis mucosa, and epithelium in serosal side of mucosa (Mc). BHSP‐binding sites over arterioles and epithelium are shown in higher power in Fig. 6A. BHSK‐binding sites were detectable only in inner circular muscle. Bar, 1.07 mm.



Figure 8.

BHSP‐binding sites in mucosal epithelium in ileum (a, b) and appendix (c, d). Panels a and c: hematoxylin and eosin‐stained sections of ileum and appendix, respectively; b and d: dark‐field autoradiograms showing distribution of SP‐binding sites. In both ileum and appendix, epithelium on serosal side of mucosa contains a moderate‐to‐heavy concentration of SP‐binding sites. In addition, binding sites can be observed in the muscularis mucosa (MM), inner circular muscle (iCM), and myenteric plexus (MP) in the ileum and the muscularis mucosa and inner circular muscle in the appendix. A, arteriole; Mc, mucosa. Bar, 1.10 mm.



Figure 9.

Localization of BHSP‐ and BHSK‐binding sites in canine colon. Note high concentration of BHSP‐binding sites associated with longitudinal muscle (LM), circular muscle (CM), arterioles (A), muscularis mucosa (MM), base of the mucosa (Muc), and the germinal (g) but not the proliferative (p) layer of lymph nodule (Lym). Bar, 0.95 mm.

See Fig. 1A for further explanation


Figure 10.

that express BHSP receptor‐binding sites. In lymph nodule only lightly stained germinal center (g) is labeled, while the more darkly hematoxylin and eosin‐stained proliferative zone (p) is unlabeled. Binding sites expressed by arterioles include both the smooth muscle and the endothelial cells that border on lumen. CM, circular muscle; MM, muscularis mucosa. Bar, 0.85 mm.

See Fig. 1A for further explanation


Figure 11.

Localization of BHSP‐binding sites in lymph nodules (Lym) that are located in basal mucosa in antrum of dog. As in lymph nodule shown in Fig. 10A, BHSP‐binding sites are associated with lightly stained germinal center rather than more darkly stained proliferative zone. A, arteriole. Bar, 0.75 mm.

See Fig. 1A for further explanation


Figure 12.

Dark‐field autoradiograms showing distribution of binding sites of substance P (SP) in transverse sections of colon obtained from margins of extensive resection for carcinoma (a) and from patients with Crohn's disease (b) and ulcerative colitis (c). Whereas in normal colon (a) a moderate concentration of SP receptor‐binding sites is expressed by external circular muscle (CM) and tunica media of a large artery in the serosa, in colon affected by either Crohn's disease (b) or ulcerative colitis (c), arterioles, venules, and lymph nodules express very high levels of SP receptor‐binding sites. LM, longitudinal muscle. Bar, 1.4 mm.



Figure 13.

Histogram showing changes in location and concentration of SP‐ and SK‐binding sites in surgical specimens of human colon obtained from carcinoma resection (open bars), Crohn's disease (hatched bars), and ulcerative colitis (solid bars). In this histogram, 100% specific binding is that concentration of specific SP‐binding sites expressed by smooth muscle (SM) of normal external circular muscle (CM). Although SP receptor‐binding sites are undetectable in blood vessels (bv) vascularizing the circular and longitudinal muscle (LM) and in lymph nodules of normal patients, in Crohn's and ulcerative colitis patients they reach levels that are the highest observed in the human gastrointestinal tract. Distinct binding sites for neuromedin K were not detected in any area of the human gastrointestinal tract.

 1. Affolter, H.‐U., A. C., Young, and T. I. Bonner, Structural organization of the human and rat tachykinin genes (Abstract). Soc. Neurosci. Abstr. 11: 1115, 1985.
 2. Amin, A. H., T. B. B., Crawford, and J. H. Gaddum, The distribution of substance P and 5‐hydroxy‐tryptamine in the central nervous system of the dog. J. Physiol. Lond. 126: 596–618, 1954.
 3. Anastasi, A., and V. Erspamer, Occurrence and some properties of eledoisin in extracts of posterior salivary glands of Eledone. Br. J. Pharmacol. 19: 326–336, 1962.
 4. Anastasi, A., V., Erspamer, and R. Endean, Structure of uperolein, a physalaemin‐like endecapeptide occurring in the skin of Uperoleia rugosa and Uperoleia marmorata. Experientia Basel 31: 394–395, 1975.
 5. Anastasi, A., and G. Falconieri Erspamer, Occurrence of phyllomedusin, a physalaemin‐like decapeptide in the skin of Phyllomedusa bicolor. Experientia Basel 26: 866–867, 1970.
 6. Anastasi, A., P., Montecucchi, V. Erspamer, and J. Visser, Amino acid composition and sequence of kassinin, a tachykinin dodecapeptide from the skin of the African frog Kassina senegalensis. Experientia Basel 33: 857–858, 1977.
 7. Bahouth, S. W., D. M., Lazaro, D. E. Brundish, and J. M. Musacchio, Specific binding of [3H‐Tyr8]physalaemin to rat submaxillary gland substance P receptor. Mol. Pharmacol. 27: 38–45, 1985.
 8. Balfe, A., P., Skrabanek, and D. Powell, Heterogeneous molecular forms of circulating substance P. In: Substance P—Dublin 1983, edited by P. Skrabanek and D. Powell. Dublin: Boole, 1983, p. 168–169.
 9. Baron, S. A., B. M., Jaffe, and A. R. Gintzler, Release of substance P from the enteric nervous system: direct quantitation and characterization. J. Pharmacol. Exp. Ther. 227: 365–368, 1983.
 10. Barthó, L., and P. Holzer, Search for a physiological role of substance P in gastrointestinal motility. Neuroscience 16: 1–32, 1985.
 11. Beleslin, D., and V. Varagić, The effect of substance P on the peristaltic reflex of the isolated guinea‐pig ileum. Br. J. Pharmacol. 13: 321–325, 1958.
 12. Bernstein, J. E., and J. R. Hamill, Substance P (Letter to editor). J. Invest. Dermatol. 77: 250, 1981.
 13. Berridge, M. J., Rapid accumulation of inositol triphosphate reveals that agonists hydrolyse polyphosphoinositides instead of phosphatidylinositol. Biochem. J. 212: 849–858, 1983.
 14. Berridge, M. J., Inositol trisphosphate and diacylglycerol as second messengers. Biochem. J. 220: 345–360, 1984.
 15. Bertaccini, G., Active peptides of nonmammalian origin. Pharmacol. Rev. 28: 127–177, 1976.
 16. Boissonnas, R. A., J., Franz, and E. Stürmer, On the chemical characterization of substance P. Ann. NY Acad. Sci. 104: 376–377, 1963.
 17. Bradbury, A. F., M. D. A., Finnie, and D. G. Smythe, Mechanisms of C‐terminal amide formation by pituitary enzymes. Nature Lond. 228: 686–688, 1982.
 18. Brodin, E., J., Alumets, R. Håkanson, S. Leander, and F. Sundler, Immunoreactive substance P in the chicken gut: distribution, development and possible functional significance. Cell Tissue Res. 216: 455–469, 1981.
 19. Brodin, E., and G. Nilsson, Concentration of substance P‐like immunoreactivity (SPLI) in tissues of dog, rat and mouse. Acta Physiol. Scand. 112: 305–312, 1981.
 20. Brown, C. L., and M. R. Hanley, The effects of substance P and related peptides on α‐amylase release from rat parotid gland slices. Br. J. Pharmacol. 73: 517–523, 1981.
 21. Buck, S. H., E., Burcher, C. W. Shults, W. Lovenberg, and T. L. O'Donohue, Novel pharmacology of substance K binding sites: a third type of tachykinin receptor. Science Wash. DC 226: 987–989, 1984.
 22. Buck, S. H., Y., Maurin, T. F. Burks, and H. I. Yamamura, High affinity 3H‐substance P binding to longitudinal muscle membranes of the guinea‐pig small intestine. Life Sci. 34: 497–506, 1983.
 23. Burcher, E., C. W., Shults, S. H. Buck, T. N. Chase, and T. L. O'Donohue, Autoradiographic distribution of substance K binding sites in rat gastrointestinal tract: a comparison with substance P. Eur. J. Pharmacol. 102: 561–562, 1984.
 24. Bury, R. W., and M. L. Mashford, Biological activity of C‐terminal partial sequences of substance P. J. Med. Chem. 854–856, 1976.
 25. Bury, R. W., and M. L. Mashford, Interactions between local anesthetics and spasmogens on the guinea‐pig ileum. J. Pharmacol Exp. Ther. 197: 633–640, 1976.
 26. Bury, R. W., and M. L. Mashford, A pharmacological investigation of synthetic substance P on the isolated guinea‐pig ileum. Clin. Exp. Pharmacol. Physiol. 4: 453–461, 1977.
 27. Cascieri, M. A., G. G., Chicchi, and T. Liang, Demonstration of two distinct‐tachykinin receptors in rat brain cortex. J. Biol. Chem. 260: 1501–1507, 1985.
 28. Chahl, L. A., Effects of substance P antagonists on the atropine‐sensitive and atropine‐resistant responses of guinea‐pig ileum to substance P. Neurosci. Lett. 55: 35–40, 1985.
 29. Chang, M. M., and S. E. Leeman, Isolation of a sialogogic peptide from bovine hypothalamic tissue and its characterization as substance P. J. Biol. Chem. 245: 4784–4790, 1970.
 30. Chang, M. M., S. E., Leeman, and H. D. Niall, Amino acid sequence of substance P. Nature New Biol. 232: 86–87, 1971.
 31. Chiba, T., T., Taminato, S. Kadowaki, T. Fujita, Y. Seino, H. Imura, and N. Yanaihara, Somatostatin and gastrin release from isolated perfused rat stomach. In: Gut Hormones: Secretion, Function and Clinical Aspects, edited by A. Miyoshi and M. I. Grossman. Amsterdam: Elsevier, 1979, p. 233–236.
 32. Conlon, J. M., G., Schäfer, W. E. Schmidt, L. H. Lazarus, H. D. Becker, and W. Creutzfeldt, Chemical and immunochemical characterization of substance P‐like immuno‐reactivity and physalaemin‐like immunoreactivity in a carcinoid tumour. Regul. Pept. 11: 117–132, 1985.
 33. Costa, M., A. C., Cuello, J. B. Furness, and R. Franco, Distribution of enteric neurons showing immunoreactivity for substance P in the guinea‐pig ileum. Neuroscience 5: 323–331, 1980.
 34. Costa, M., J. B., Furness, R. Franco, I. J. Llewellyn‐Smith, R. Murphy, and A. M. Beardsley, Substance P in nerve tissue in the gut. In: Substance P in the Nervous System, edited by R. Porter and M. O'Connor. London: Pitman, 1982, p. 129–144. (Ciba Found. Symp. 91.)
 35. Costa, M., J. B., Furness, I. J. Llewellyn‐Smith, and A. C. Cuello, Projections of substance P‐containing neurons within the guinea‐pig small intestine. Neuroscience 6: 411–424, 1981.
 36. Costa, M., J. B., Furness, I. J. Llewellyn‐Smith, R. Murphy, J. C. Bornstein, and J. R. Keast, Functional roles for substance P‐containing neurones in the gastrointestinal tract. In: Substance P: Metabolism and Biological Actions, edited by C. C. Jordan and P. Oehme. London: Taylor & Francis, 1985, p. 99–119.
 37. Costa, M., J. B., Furness, C. O. Pullin, and J. Bornstein, Substance P enteric neurons mediate non‐cholinergic transmission to the circular muscle of the guinea‐pig intestine. Naunyn‐Schmiedeberg's Arch. Pharmacol. 328: 446–453, 1985.
 38. Couture, R., A., Fournier, J. Magnan, S. St.‐Pierre, and D. Regoli, Structure‐activity studies on substance P. Can. J. Physiol. Pharmacol. 57: 1427–1436, 1979.
 39. Creba, J. A., C. P., Downes, P. T. Hawkins, G. Brewster, R. H. Michell, and C. J. Kirk, Rapid breakdown of phosphatidylinositol‐4‐phosphate and phosphatidylinositol‐4,5‐bisphosphate in rat hepatocytes stimulated by vasopressin and other Ca++ mobilizing hormones. Biochem. J. 212: 733–747, 1983.
 40. Daniel, E. E., T., Gonda, T. Domoto, and M. Oki, The effects of substance P and met5‐enkephalin in dog ileum. Can. J. Physiol. Pharmacol. 60: 830–840, 1982.
 41. De Caro, G., M. Massi, and L. G. Micossi, Modifications of drinking behaviour and of arterial blood pressure induced by tachykinins in rats and pigeons. Psychopharmacology 68: 243–247, 1980.
 42. Deutch, A. Y., J. E., Maggio, M. J. Bannon, P. W. Kaltvas, S.‐Y. Tam, M. Goldstein, and R. H. Roth, Substance K and substance P differentially modulate mesolimbic and mesocortical systems. Peptides Fayetteville 6, Suppl. 2: 113–122, 1985.
 43. Donnerer, J., L., Barthó, P. Holzer, and F. Lembeck, Intestinal peristalsis associated with release of immunoreactive substance P. Neuroscience 11: 913–918, 1984.
 44. Douglas, W. W., W., Feldberg, W. D. M. Paton, and M. Schachter, Distribution of histamine and substance P in the wall of dogs digestive tract. J. Physiol. Lond. 115: 163–176, 1951.
 45. Downes, C. P., and M. M. Wusteman, Breakdown of polyphosphoinositides and not phosphatidylinositol accounts for muscarinic agonist‐stimulated inositol phospholipid metabolism in rat parotid glands. Biochem. J. 216: 633–640, 1983.
 46. Edin, R., J. M., Lundberg, P. Lidberg, A. Dahlström, and H. Ahlman, Atropine‐sensitive contractile motor effects of substance P on the feline pylorus and stomach in vivo. Acta Physiol. Scand. 110: 207–209, 1980.
 47. Eliasson, R., L., Lie, and B. Pernow, A comparative study of substance P from intestine and brain. Br. J. Pharmacol. 11: 137–140, 1956.
 48. Erspamer, V., Ricerche preliminaria sulla moschatina. Experientia Basel 5: 79–81, 1949.
 49. Erspamer, V., Biogenic amines and active polypeptides of the amphibian skin. Annu. Rev. Pharmacol. 11: 327–350, 1971.
 50. Erspamer, V., The tachykinin peptide family. Trends Neurosci. 4: 267–269, 1981.
 51. Erspamer, V., and A. Anastasi, Structure and pharmacological actions of eledoisin, the active endecapeptide of the posterior salivary glands of Eledone. Experientia Basel 18: 58–59, 1962.
 52. Erspamer, V., and A. Anastasi, Polypeptides active on plain muscle in the amphibian skin. In: Hypotensive Peptides, edited by E. G. Erdös, N. Back, F. Sicuteri, and A. F. Wilde. New York: Springer‐Verlag, 1966, p. 63–75.
 53. Erspamer, V., A., Anastasi, G. Bertaccini, and J. M. Cei, Structure and pharmacological actions of physalaemin, the main active polypeptide of the skin of Physalaemus fuscumaculatus. Experientia Basel 20: 489–490, 1964.
 54. Erspamer, V., and G. Falconieri Erspamer, Pharmacological actions of eledoisin on extravascular smooth muscle. Br. J. Pharmacol. 19: 337–354, 1962.
 55. Erspamer, V., and P. Melchiorri, Active peptides of the amphibian skin and their synthetic analogs. Pure Appl. Chem. 35: 463–494, 1973.
 56. Erspamer, V., and P. Melchiorri, Active polypeptides: from amphibian skin to gastrointestinal tract and brain of mammals. Trends Pharmacol. Sci. 1: 391–395, 1980.
 57. Escher, E., P., D'Orleans‐Juste, S. Dion, G. Drapeau, J. Mizrahi, and D. Regoli, A substance P antagonist not containing D‐tryptophan. Eur. J. Pharmacol. 105: 375–377, 1984.
 58. Euler, U. S. VON, Untersuchungen über Substanz P, die atropinfester, darmerregende und gefässerweiternde Substanz aus Darm und Gehirn. Naunyn‐Schmiedebergs Arch. Exp. Pathol. Pharmakol. 181: 181–197, 1936.
 59. Euler, U. S. VON, Herstellung und Eigenschaften von Substanz P. Acta Physiol. Scand. 4: 373–375, 1942.
 60. Von Euler, U. S., and J. H. Gaddum, An unidentified depressor substance in certain tissue extracts. J. Physiol. Lond. 72: 74–87, 1931.
 61. Euler, U. S. Von., and E. ÖStlund, Occurrence of a substance P‐like polypeptide in fish intestine and brain. Br. J. Pharmacol. 11: 323–325, 1956.
 62. Von Euler, U. S., AND B. Pernow (editors), Substance P. New York: Raven, 1977. (Nobel Symp. Ser., no. 37.)
 63. Falconieri Erspamer, G., V. Erspamer, and D. Piccininelli, Parallel bioassay of physalaemin and kassinin, a tachykinin dodecapeptide from the skin of the African frog Kassina senegalensis. Naunyn‐Schmiedeberg's Arch. Pharmacol. 311: 61–65, 1980.
 64. Folkers, K., R., Håkanson, J. Hörig, J.‐C. Xu, and S. Leander, Biological evaluation of substance P antagonists. Br. J. Pharmacol. 83: 449–456, 1984.
 65. Fontaine‐Perus, J., M., Chanconie, J. M. Polak, and N. M. Le Douarin, Origin and development of VIP and substance P containing neurons in the embryonic avian gut. Histochemistry 71: 313–323, 1981.
 66. Fosbraey, P., R. L., Featherstone, and I. K. M. Morton, Comparison of potency of substance P and related peptides on [3H]‐acetylcholine release, and contractile actions, in the guinea‐pig ileum. Naunyn‐Schmiedeberg's Arch. Pharmacol. 326: 111–115, 1984.
 67. Franco, R., M., Costa, and J. B. Furness, Evidence for the release of endogenous substance P from intestinal nerves. Naunyn‐Schmiedeberg's Arch. Pharmacol. 306: 195–201, 1979.
 68. Franco, R., M., Costa, and J. B. Furness, Evidence that axons containing substance P in the guinea‐pig ileum are of intrinsic origin. Naunyn‐Schmiedeberg's Arch. Pharmacol. 307: 57–63, 1979.
 69. Furness, J. B., M., Costa, and J. R. Keast, Choline acetyl‐transferase‐ and peptide immunoreactivity of submucous neurons in the small intestine of the guinea‐pig. Cell Tissue Res. 237: 329–336, 1984.
 70. Furness, J. B., R. E., Papka, N. G. Della, M. Costa, and R. L. Eskay, Substance P‐like immunoreactivity in nerves associated with the vascular system of guinea‐pigs. Neuroscience 7: 447–459, 1982.
 71. Gaddum, J. H., Tryptamine receptors. J. Physiol. Lond. 119: 363–368, 1953.
 72. Gaddum, J. H., and H. Schild, Depressor substances in extracts of intestine. J. Physiol. Lond. 83: 1–14, 1934.
 73. Gaddum, J. H., and J. C. Szerb, Assay of substance P on goldfish intestine in a microbath. Br. J. Pharmacol. 17: 451–463, 1961.
 74. Gamse, R., E., Mroz, S. E. Leeman, and F. Lembeck, The intestine as source of immunoreactive substance P in plasma of the cat. Naunyn‐Schmiedeberg's Arch. Pharmacol. 305: 17–21, 1978.
 75. Garfield, E., ABCs of cluster mapping. Part 1. Most active fields in the life sciences 1978. Curr. Contents 40: 5–12, 1980.
 76. Gater, P. R., C. C., Jordon, and D. G. Owen, Relative activities of substance P‐related peptides in the guinea‐pig ileum and rat parotid gland, in vitro. Br. J. Pharmacol. 75: 341–348, 1982.
 77. Gernandt, B., Untersuchung über die biologische Wirkung der Substanz P. Acta Physiol. Scand. 3: 270–274, 1942.
 78. Gershon, M. D., The enteric nervous system. Annu. Rev. Neurosci. 4: 227–272, 1981.
 79. Grabner, K., F., Lembeck, and K. Neuhold, Substanz P im Gehirn verschiedener Species. Naunyn‐Schmiedebergs Arch. Exp. Pathol. Pharmakol. 236: 331–334, 1959.
 80. Growcott, J. W., A., Jamieson, A. V. Tarpey, and L. D. Topham, Further evidence for multiple tachykinin receptors. Eur. J. Pharmacol. 86: 59–64, 1983.
 81. Growcott, J. W., and A. V. Tarpey, Evidence that [D‐Pro2,D‐Trp7,9]SP, a putative substance P antagonist, is an antagonist at “E”‐type receptors (Abstract). Br. J. Pharmacol. 78: 79P, 1983.
 82. Güllner, H.‐G., H., Yajima, D. Herbert, and W. W. Owen, Growth hormone, prolactin, and FSH release by the tachykinin dodecapeptide kassinin in the rat. Arch. Int. Pharmacodyn. Ther. 256: 4–9, 1982.
 83. Håkanson, R., S., Bengmark, E. Brodin, S. Ingemansson, L. I. Larsson, G. Nillson, and F. Sundler, Substance P‐like immunoreactivity in intestinal carcinoid tumors. In: Substance P, edited by U. S. Von Euler and B. Pernow. New York: Raven, 1977, p. 55–58. (Nobel Symp. Ser., no. 37.)
 84. Hanley, M. R., C.‐M., Lee, L. M. Jones, and R. H. Michell, Similar effects of substance P and related peptides on salivation and on phosphatidylinositol turnover in rat salivary glands. Mol. Pharmacol. 18: 78–83, 1980.
 85. Harmar, A. J., A., Armstrong, C.‐M. Lee, and P. C. Emson, Characterization and partial purification of a 5700 dalton form of substance P‐like immunoreactivity from the rat hypothalamus. Brain Res. 323: 342–344, 1984.
 86. Harmar, A. J., and P. Keen, Rat sensory ganglia incorporate radiolabeled amino acids into substance K. Neurosci. Lett. 51: 387–391, 1984.
 87. Harmar, A., J. G., Schofield, and P. Keen, Cycloheximide‐sensitive synthesis of substance P by isolated dorsal root ganglia. Nature Lond. 284: 267–269, 1980.
 88. Harmar, A. J., J. G., Schofield, and P. Keen, Substance P biosynthesis in dorsal root ganglia: an immunochemical study of [35S]methionine and [3H]proline incorporation in vitro. Neuroscience 6: 1917–1922, 1981.
 89. Heitz, P., J. M., Polak, C. M. Timsom, and A. G. E. Pearse, Enterochromaffin cells as the endocrine source of gastrointestinal substance P. Histochemistry 49: 343–347, 1976.
 90. Hermansen, K., Effects of substance P and other peptides on the release of somatostatin, insulin and glucagon in vitro. Endocrinology 107: 256–261, 1980.
 91. Hökfelt, T., M., Schultzberg, R. Elde, G. Nilsson, L. Terenius, S. Said, and M. Goldstein, Peptide neurons in peripheral tissues including the urinary tract: immunohistochemical studies. Acta Pharmacol. Toxicol. 43: 79–89, 1978.
 92. Holmgren, S., D. J., Grove, and S. Nilsson, Substance P acts by releasing 5‐hydroxytryptamine from enteric neurons in the stomach of the rainbow trout, Salmo gairdneri. Neuroscience 14: 683–693, 1985.
 93. Holzer, P., Characterization of the stimulus‐induced release of immunoreactive substance P from the myenteric plexus of the guinea‐pig small intestine. Brain Res. 297: 127–136, 1984.
 94. Holzer, P., Stimulation and inhibition of gastrointestinal propulsion induced by substance P and substance K in the rat. Br. J. Pharmacol. 86: 305–312, 1985.
 95. Holzer, P., P. C., Emson, M. Holzbauer, L. L. Iversen, and D. F. Sharman, Tissue distribution of substance P in the domestic pig postnatal development. Dev. Brain Res. 1: 455–459, 1981.
 96. Holzer, P., P. C., Emson, L. L. Iversen, and D. F. Sharman, Regional differences in the response to substance P of the longitudinal muscle and the concentration of substance P in the digestive tract of the guinea‐pig. Neuroscience 6: 1433–1441, 1981.
 97. Holzer, P., R., Gamse, and F. Lembeck, Distribution of substance P in the rat gastrointestinal tract—lack of effect of capsaicin pretreatment. Eur. J. Pharmacol. 61: 303–307, 1980.
 98. Holzer, P., and F. Lembeck, Neurally‐mediated contraction of ileal longitudinal muscle by substance P. Neurosci. Lett. 17: 101–105, 1980.
 99. Holzer, P., and I. T. Lippe, Substance P action on phosphoinositides in guinea‐pig intestinal muscle: a possible transduction mechanism? Naunyn‐Schmiedeberg's Arch. Pharmacol. 329: 50–55, 1985.
 100. Holzer‐Petsche, U., E., Schimek, R. Amann, and F. Lembeck, In vivo and in vitro actions of mammalian tachykinins. Naunyn‐Schmiedeberg's Arch. Pharmacol. 330: 130–135, 1985.
 101. Hunter, J. C., M., Goedert, and R. D. Pinnock, Mammalian tachykinin‐induced hydrolysis of inositol phospholipids in rat brain slices. Biochem. Biophys. Res. Commun. 127: 616–622, 1985.
 102. Hunter, J. C., P. A., Hannah, and J. E. Maggio, The regional distribution of kassinin‐like immunoreactivity in central and peripheral tissues of the cat. Brain Res. 341: 228–232, 1985.
 103. Hunter, J. C., and J. E. Maggio, Pharmacological characterization of a novel tachykinin isolated from mammalian spinal cord. Eur. J. Pharmacol. 97: 159–160, 1984.
 104. Hunter, J. C., and J. E. Maggio, A pharmacological study with substance K: evidence for multiple types of tachykinin receptors. Eur. J. Pharmacol. 105: 149–153, 1984.
 105. Jensen, R. T., and J. D. Gardner, Interaction of physalaemin, substance P, and eledoisin with specific membrane receptors of pancreatic acinar cells. Proc. Natl. Acad. Sci. USA 76: 5679–5683, 1979.
 106. Jensen, R. T., S. W., Jones, K. Folkers, and J. D. Gardner, A synthetic peptide that is a bombesin antagonist. Nature Land. 309: 61–63, 1984.
 107. Jessell, T. M., Substance P in the nervous system. In: Handbook of Psychopharmacology. Neuropeptides, edited by L. L. Iversen, S. D. Iversen, and S. H. Snyder. New York: Plenum, 1983, vol. 16, p. 1–105.
 108. Jordan, C. C., AND P. Oehme (editors), Substance P: Metabolism and Biological Actions. London: Taylor & Francis, 1985.
 109. Kachur, J. F., R. J., Miller, M. Field, and J. Rivier, Neurohumoral control of ileal electrolyte transport. II. Neurotensin and substance P. J. Pharmacol. Exp. Ther. 220: 456–463, 1982.
 110. Kanazawa, I., T., Ogawa, S. Kimura, and E. Munekata, Regional distribution of substance P, neurokinin α and neurokinin β in rat central nervous system. Neurosci. Res. 2: 111–120, 1984.
 111. Kangawa, K., N., Minamino, A. Fukuda, and H. Matsuo, Neuromedin K: a novel mammalian tachykinin identified in porcine spinal cord. Biochem. Biophys. Res. Commun. 114: 533–540, 1983.
 112. Katayama, Y., and R. A. North, Does substance P mediate slow synaptic excitation within the myenteric plexus? Nature Lond. 274: 387–388, 1978.
 113. Katayama, Y., R. A., North, and J. T. Williams, The action of substance P on neurons of the myenteric plexus of the guinea‐pig small intestine. Proc. R. Soc. Lond. B Biol. Sci. 206: 191–208, 1979.
 114. Keast, J. R., J. B., Furness, and M. Costa, Origins of peptide and norepinephrine nerves in the mucosa of the guinea‐pig small intestine. Gastroenterology 86: 637–644, 1984.
 115. Keast, J. R., J. B., Furness, and M. Costa, Different substance P receptors are found on mucosal epithelial cells and submucous neurons of the guinea‐pig small intestine. Naunyn‐Schmiedeberg's Arch. Pharmacol. 329: 382–387, 1985.
 116. Kimura, S., K., Goto, T. Ogawa, Y. Sugita, and I. Kanazawa, Pharmacological characterization of novel mammalian tachykinins, neurokinin α and neurokinin β. Neurosci. Res. 2: 97–104, 1984.
 117. Kimura, S., T., Ogawa, K. Goto, Y. Sugita, E. Munekata, and I. Kanazawa, Endogenous ligands for tachykinin receptors in mammals. In: Substance P: Metabolism and Biological Actions, edited by C. C. Jordan and P. Oehme. London: Taylor & Francis, 1985, p. 33–43.
 118. Kimura, S., M., Okada, Y. Sugita, I. Kanazawa, and E. Munekata, Novel neuropeptides, neurokinins α and β, isolated from porcine spinal cord. Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci. 59: 101–104, 1983.
 119. Kishimoto, A., Y., Takai, T. Mori, U. Kikkawa, and Y. Nishizuka, Activation of calcium and phospholipid‐dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover. J. Biol. Chem. 255: 2273–2276, 1980.
 120. Krause, J. E., On the physiological metabolism of substance P. In: Substance P: Metabolism and Biological Actions, edited by C. C. Jordan and P. Oehme. London: Taylor & Francis, 1985, p. 13–31.
 121. Krause, J. E., A. J., Reiner, J. P. Advis, and J. F. Mckelvy, In vivo biosynthesis of [35S]‐ and [3H]substance P in the striatum of the rat and their axonal transport to the substantia nigra. J. Neurosci. 4: 775–785, 1984.
 122. Kream, R. M., T. A., Schoenfeld, R. Mancuso, A. N. Clancy, W. El‐Bermani, and F. Macrides, Precursor forms of substance P (SP) in nervous tissue: detection with antisera to SP, SP‐Gly, and SP‐Gly‐Lys. Proc. Natl. Acad. Sci. USA 82: 4832–4836, 1985.
 123. Kuo, J. F., R. G. G., Andersson, B. C. Wise, L. Mackerlova, I. Salmonsson, N. L. Brackett, N. Katoh, M. Schoji, and R. W. Wrenn, Calcium‐dependent protein kinase: widespread occurrence in various tissues and phyla of the animal kingdom and comparison of effects of phospholipid, calmodulin and trifluoperazine. Proc. Natl. Acad. Sci. USA 77: 7039–7043, 1980.
 124. Larsson, L. I., Innervation of the pancreas by substance P, enkephalin, vasoactive intestinal polypeptide and gastrin/CCK immunoreactive nerves. J. Histochem. Cytochem. 27: 1283–1284, 1979.
 125. Laufer, R., U., Wormser, Z. Y. Friedman, C. Gilon, M. Chorev, and Z. Selinger, Neurokinin B is a preferred agonist for a neuronal substance P receptor and its action is antagonized by enkephalin. Proc. Natl. Acad. Sci. USA 82: 7444–7448, 1985.
 126. Lazarus, L. H., R. I., Linnoila, O. Hernandez, and R. P. Diaugustine, A neuropeptide in mammalian tissues with physalaemin‐like immunoreactivity. Nature Lond. 287: 555–558, 1980.
 127. Lazarus, L. H., W. E., Wilson, G. Gaudino, B. J. Irons, and A. Guglietta, Evolutionary relationship between nonmammalian and mammalian peptides. Peptides Fayetteville 6, Suppl. 3: 295–307, 1985.
 128. Leander, S., E., Brodin, R. Håkanson, F. Sundler, and R. Uddman, Neuronal substance P in the esophagus. Distribution and effects on motor activity. Acta Physiol. Scand. 115: 427–435, 1982.
 129. Leander, S., R., Håkanson, and F. Sundler, Nerves containing substance P, vasoactive intestinal polypeptide, enkephalin or somatostatin in the guinea‐pig taenia coli. Cell Tissue Res. 215: 21–39, 1981.
 130. Lee, C.‐M., L. L., Iversen, M. R. Hanley, and B. E. B. Sandberg, The possible existence of multiple receptors for substance P. Naunyn‐Schmiedeberg's Arch. Pharmacol. 318: 281–287, 1982.
 131. Leeman, S. E., and R. E. Carraway, The discovery of a sialogogic peptide in bovine hypothalamic extracts: its isolation, characterization as substance P, structure and synthesis. In: Substance P, edited by U. S. Von Euler and B. Pernow. New York: Raven, 1977, p. 5–13. (Nobel Symp. Ser., no. 37.)
 132. Leeman, S. E., and R. Hammerschlag, Stimulation of salivary secretion by a factor from hypothalamic tissue. Endocrinology 81: 803–810, 1967.
 133. Lehy, T., and M. L. Cristina, Ontogeny and distribution of certain endocrine cells in the human fetal large intestine. Cell Tissue Res. 203: 415–425, 1979.
 134. Lembeck, F., Zur Frage der zentralen Übertragung afferenter Impulse. III. Das Vorkommen und die Bedeutung der Substanz P in den dorsalen Wurzeln des Rückenmarks. Naunyn‐Schmiedebergs Arch. Exp. Pathol. Pharmakol. 219: 197–213, 1953.
 135. Lembeck, F., and P. Holzer, Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation. Naunyn‐Schmiedeberg's Arch. Pharmacol. 310: 175–183, 1979.
 136. Lembeck, F., and K. Starke, Substanz P und Speichelsekrection. Naunyn‐Schmeidebergs Arch. Exp. Pathol. Pharmakol. 259: 375–385, 1968.
 137. Lembeck, F., and G. Zetler, Substance P. A polypeptide of possible physiological significance especially within the nervous system. Int. Rev. Neurobiol. 4: 159–215, 1962.
 138. Lembeck, F., and G. Zetler, Substance P. In: Pharmacology of Naturally Occurring Polypeptides and Lipid‐Soluble Acids, edited by J. M. Walker. Oxford, UK: Pergamon, 1971, p. 29–72.
 139. Liang, T., and M. A. Cascieri, Substance P stimulation of amylase release by isolated parotid cells and inhibition of substance P induction of salivation by vasoactive peptides. Mol. Cell. Endocrinol. 15: 151–162, 1979.
 140. Liang, T., and M. A. Cascieri, Specific binding of an immunoreactive and biologically active 125I‐labeled N(1)‐acylated substance P derivative to parotid cells. Biochem. Biophys. Res. Commun. 96: 1793–1799, 1980.
 141. Liang, T., and M. A. Cascieri, Substance P receptor on parotid cell membranes. J. Neurosci. 1: 1133–1141, 1981.
 142. Llewellyn‐Smith, I. J., J. B., Furness, R. Murphy, P. E. O'Brien, and M. Costa, Substance P‐containing nerves in the human small intestine: distribution, ultrastructure, and characterization of the immunoreactive peptide. Gastroenterology 86: 421–435, 1984.
 143. Lundberg, J. M., T. Hökfelt, A. Änggård, K. Uvnäs‐Wallensten, S. Brimijoin, E. Brodin, and J. Fahrenkrug, Peripheral peptide neurons; distribution, axonal transport and some aspects on possible function. In: Neural Peptides and Neuronal Communication, edited by E. Costa and M. Trabucchi. New York: Raven, 1980, p. 25–36.
 144. Lundqvist, I., F., Sundler, B. Ahren, J. Alumets, and R. Håkanson, Somatostatin, pancreatic polypeptide, substance P and neurotension: cellular distribution and effects on stimulated insulin secretion in the mouse. Endocrinology 104: 832–838, 1979.
 145. Maggi, C. A., S., Giuliani, P. Santicioli, D. Regoli, and A. Meli, Comparison of the effects of substance P and substance K on blood pressure, salivation and urinary bladder motility in urethane‐anaesthesized rats. Eur. J. Pharmacol. 113: 291–294, 1985.
 146. Maggio, J. E., Kassinin in mammals: the newest tachykinins. Peptides Fayetteville 6, Suppl. 3: 237–243, 1985.
 147. Maggio, J. E., and J. C. Hunter, Regional distribution of kassinin‐like immunoreactivity in rat central and peripheral tissues and the effect of capsaicin. Brain Res. 307: 370–373, 1984.
 148. Maggio, J. E., C. R., Mantyh, and P. W. Mantyh, Tachykinin receptors in mammals (Abstract). Soc. Neurosci. Abstr. 11: 415, 1985.
 149. Maggio, J. E., B. E. B., Sandberg, C. V. Bradley, L. L. Iversen, S. Santikarn, D. H. Williams, J. C. Hunter, and M. R. Hanley, Substance K: a novel tachykinin in mammalian spinal cord. In: Substance P—Dublin 1983, edited by P. Skrabanek and D. Powell. Dublin: Boole, 1983, p. 20–21.
 150. Magnusson, I., L., Thulin, H. Samnegård, G. Tydén, and S. Efendic, Anticholeretic effects of substance P and somatostatin (Abstract). Regul. Pept. 1, Suppl.: 72, 1980.
 151. Malmfors, G., S., Leander, E. Brodin, R. Håkanson, T. Holmin, and F. Sundler, Peptide‐containing neurons intrinsic to the gut wall. An experimental study in the pig. Cell Tissue Res. 214: 225–238, 1981.
 152. Mantyh, P. W., M., Goedert, and S. P. Hunt, Autoradiographic localization of receptor binding sites for substance P in the gastrointestinal tract and periphery of the guinea‐pig (Abstract). Soc. Neurosci. Abstr. 10: 214, 1984.
 153. Mantyh, P. W., M., Goedert, and S. P. Hunt, Autoradiographic visualization of receptor binding sites for substance P in the gastrointestinal tract of the guinea‐pig. Eur. J. Pharmacol. 100: 133–134, 1984.
 154. Mantyh, P. W., and S. P. Hunt, Neuropeptides are present in projection neurons at all levels in visceral and taste pathways: from periphery to sensory cortex. Brain Res. 299: 297–311, 1984.
 155. Mantyh, P. W., J. E., Maggio, and S. P. Hunt, The autoradiographic distribution of kassinin and substance K binding sites is different from the distribution of substance P binding sites in rat brain. Eur. J. Pharmacol. 102: 361–364, 1984.
 156. Mantyh, P. W., R. D., Pinnock, C. P. Downes, M. Goedert, and S. P. Hunt, Substance P receptors: correlation with substance P‐induced inositol phospholipid hydrolysis in the rat central nervous system. Nature Lond. 309: 795–797, 1984.
 157. Meinardi, H., and L. C. Craig, Studies of substance P. In: Hypotensive Peptides, edited by E. G. Erdös, N. Back, F. Sicuteri, and A. F. Wilde. New York: Springer‐Verlag, 1966, p. 594–606.
 158. Melchiorri, P., and L. Negri, Evolutionary aspects of amphibian peptides. In: Evolution and Tumour Pathology of the Neuroendocrine System, edited by S. Falkmer, R. Håkanson, and F. Sundler. New York: Elsevier, 1984, p. 231–244.
 159. Milne, R. J., R. D., Foreman, G. J. Geisler, and W. D. Willis, Convergence of cutaneous pelvic visceral nociceptive inputs onto primate spinothalamic neurons. Pain 11: 163–183, 1981.
 160. Minagawa, H., S., Shiosaka, H. Inoue, N. Hayashi, A. Kasahara, T. Kamata, M. Tohyama, and Y. Shiotani, Origins and three‐dimensional distribution of substance P‐containing structures on the rat stomach using whole‐mount tissue. Gastroenterology 86: 51–59, 1984.
 161. Minamino, N., K., Kangawa, A. Fukuda, and H. Matsuo, Neuromedin L: a novel mammalian tachykinin identified in porcine spinal cord. Neuropeptides 4: 157–166, 1984.
 162. Minamino, N., H., Masuda, K. Kangawa, and H. Matsuo, Regional distribution of neuromedin K and neuromedin L in rat brain and spinal cord. Biochem. Biophys. Res. Commun. 124: 731–738, 1984.
 163. Mizrahi, J., E., Escher, P. D'Orléans‐Juste, and D. Regoli, Undeca‐ and octa‐peptide antagonists for substance P: a study on the guinea‐pig trachea. Eur. J. Pharmacol. 99: 193–202, 1984.
 164. Nagy, J. I., S. P., Hunt, L. L. Iversen, and P. C. Emson, Biochemical and anatomical observations on the degeneration of peptide‐containing primary afferent neurons after neonatal capsaicin. Neuroscience 6: 1923–1934, 1981.
 165. Nakajima, T., T., Yasuhara, V. Erspamer, G. Falconieri Erspamer, L. Negri, and R. Endean, Physalaemin‐ and bombesin‐like peptides in the skin of the Australian leptodactylid frog Uperoleia rugosa. Chem. Pharm. Bull. Tokyo 28: 689–695, 1980.
 166. Nawa, H., M., Doteuchi, K. Igano, K. Inouye, and S. Nakanishi, Substance K: a novel mammalian tachykinin that differs from substance P in its pharmacological profile. Life Sci. 34: 1153–1160, 1984.
 167. Nawa, H., T., Hirose, H. Takashima, S. Inayama, and S. Nakanishi, Nucleotide sequences of cloned cDNAs for two types of bovine substance P precursor. Nature Lond. 306: 32–36, 1983.
 168. Nawa, H., H., Kotani, and S. Nakanishi, Tissue‐specific generation of two preprotachykinin mRNAs from one gene by alternative RNA splicing. Nature Lond. 312: 729–734, 1984.
 169. Nicoll, R. A., C., Schenker, and S. E. Leeman, Substance P as a neurotransmitter candidate. Annu. Rev. Neurosci. 3: 227–268, 1980.
 170. Nieber, K., K., Milenov, J. Bergmann, and P. Oehme, Contractile response of longitudinal and circular smooth muscles of guinea‐pig stomach and ileum to substance P. Acta Biol. Med. Ger. 40: 209–216, 1981.
 171. Nilsson, G., and E. Brodin, Tissue distribution of substance P‐like immunoreactivity in dog, cat, rat and mouse. In: Substance P, edited by U. S. Von Euler and B. Pernow. New York: Raven, 1977, p. 49–54. (Nobel Symp. Ser., no. 37.)
 172. Nilsson, G., L. I., Larsson, R. Håkanson, E. Brodin, B. Pernow, and F. Sundler, Localization of substance P‐like immunoreactivity in mouse gut. Histochemistry 43: 97–99, 1975.
 173. Nilsson, G., B., Pernow, G. H. Fisher, and K. Folkers, Presence of substance P‐like immunoreactivity in plasma from man and dog. Acta Physiol. Scand. 94: 542–544, 1975.
 174. Nishizuka, Y., The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature Lond. 308: 693–698, 1984.
 175. Norheim, L., E., Theodorsson‐Norheim, E. Brodin, K. Öberg, G. Lundqvist, and S. Rosell, Antisera raised against eledoisin and kassinin detect elevated levels of immunoreactive material in plasma and tumor tissues from patients with carcinoid tumors. Regul. Pept. 9: 245–257, 1984.
 176. Nyberg, F., P. Le, Grevés, and L. Terenius, Identification of substance P precursor forms in human brain tissue. Proc. Natl. Acad. Sci. USA 82: 3921–3924, 1985.
 177. Oehme, P., M., Bienert, K. Hecht, and J. Bergmann, Substanz P. Ausgewählte Probleme der Chemie, Biochemie, Pharmacologie, Physiologie und Pathophysiologie. Beitr. Wirkstofforsch. 12: 1–185, 1981.
 178. Otsuka, M., S., Konishi, and T. Takahashi, A further study of motoneuron‐depolarizing peptide extracted from dorsal roots of bovine spinal nerves. Proc. Jpn. Acad. 48: 747–752, 1972.
 179. Otsuka, M., S., Konishi, and T. Takahashi, The presence of a motoneuron‐depolarizing peptide in bovine dorsal roots of spinal nerves. Proc. Jpn. Acad. 48: 342–346, 1972.
 180. Pearse, A. G. E., and J. M. Polak, Immunocytochemical localization of substance P in mammalian intestine. Histochemistry 41: 373–375, 1975.
 181. Pernow, B., Substance P distribution in the digestive tract. Acta Physiol. Scand. 24: 97–102, 1951.
 182. Pernow, B., Studies on substance P. Purification, occurrence and biological actions. Acta Physiol. Scand. Suppl. 105: 1–90, 1953.
 183. Pernow, B., Pharmacology of substance P. Ann. NY Acad. Sci. 104: 393–402, 1963.
 184. Pernow, B., Substance P. Pharmacol. Rev. 35: 85–141, 1983.
 185. Piercey, M. F., P. J. K., Dobry, F. J. Einspahr, L. A. Schroeder, and N. Masiques, Use of substance P fragments to differentiate substance P receptors of different tissue. Regul. Pept. 3: 337–349, 1982.
 186. Porter, R., AND M. O'Connor (editors), Substance P in the Nervous System. London: Pitman, 1982. (Ciba Found. Symp. 91.)
 187. Quirion, R., and T.‐V. Dam, Multiple tachykinin receptors. In: Substance P: Metabolism and Biological Actions, edited by C. C. Jordan and P. Oehme. London: Taylor & Francis, 1985, p. 45–64.
 188. Rosell, S., U., Björkroth, D. Chang, I. Yamaguchi, Y.‐P. Wan, G. Rackur, G. Fisher, and K. Folkers, Effects of substance P and analogs on isolated guinea‐pig ileum. In: Substance P, edited by U. S. Von Euler and B. Pernow. New York: Raven, p. 83–88, 1977. (Nobel Symp. Ser., no. 37.)
 189. Rosell, S., U., Björkroth, J.‐C. Xu, and K. Folkers, The pharmacological profile of a substance P (SP) antagonist. Evidence for the existence of subpopulations of SP receptors. Acta Physiol. Scand. 117: 445–450, 1983.
 190. Sandberg, B. E. B., Structure‐activity relationships for substance P: a review. In: Substance P: Metabolism and Biological Actions, edited by C. C. Jordan and P. Oehme. London: Taylor & Francis, 1985, p. 65–81.
 191. Sandberg, B. E. B., and L. L. Iversen, Substance P. J. Med. Chem. 25: 1090–1095, 1982.
 192. Saria, A., E., Theodorsson‐Norheim, R. Gamse, and J. M. Lundberg, Release of substance P‐ and substance K‐like immunoreactivities from the isolated perfused guinea‐pig lung. Eur. J. Pharmacol. 106: 207–208, 1985.
 193. Schultzberg, M., C. F., Dreyfus, M. D. Gershon, T. Hökfelt, R. P. Elde, G. Nilsson, S. Said, and M. Goldstein, VIP‐, enkephalin‐, substance P‐, and somatostatin‐like immunoreactivity in neurons intrinsic to the intestine: immunohistochemical evidence from organotypic tissue cultures. Brain Res. 155: 239–248, 1978.
 194. Schultzberg, M., T., Hökfelt, G. Nilsson, L. Terenius, J. F. Rehfeld, M. Brown, R. Elde, M. Goldstein, and S. Said, Distribution of peptide‐ and catecholamine‐containing neurons in the gastro‐intestinal tract of rat and guinea‐pig: immunohistochemical studies with antisera to substance P, vasoactive intestinal polypeptide, enkephalins, somatostatin, gastrin/cholecystokinin, neurotensin and dopamine β‐hydroxylase. Neuroscience 5: 689–744, 1980.
 195. Segawa, T., Y., Nakata, and A. Inoue, Precursors for Substance P. In: Substance P: Metabolism and Biological Actions, edited by C. C. Jordan and P. Oehme. London: Taylor & Francis, 1985, p. 1–12.
 196. Sharkey, K. A., R. G., Williams, and G. J. Dockray, Sensory substance P innervation of the stomach and pancreas: demonstration of capsaicin‐sensitive neurons in rat by combined immunohistochemistry and retrograde tracing. Gastroenterology 87: 914–921, 1984.
 197. Shults, C. W., R., Quirion, B. Chronwall, T. N. Chase, and T. L. O'Donohue, A comparison of the anatomical distribution of substance P and substance P receptors in the rat central nervous system. Peptides Fayetteville 5: 1097–1128, 1984.
 198. Sjödin, L., T. P., Conlon, C. Gustavson, and K. Uddholm, Interaction of substance P with dispersed pancreatic acinar cells from the guinea‐pig. Stimulation of calcium outflux, accumulation of cyclic GMP and amylase release. Acta Physiol. Scand. 109: 107–110, 1980.
 199. Skrabanek, P., Eye of newt and toe of frog: substance P and the charmed pot of neuropeptides. Ir. J. Med. Sci. 153: 47–59, 1984.
 200. Skrabanek, P., D., Cannon, J. Kirrane, D. Legge, and D. Powell, Circulating immunoreactive substance P in man. Ir. J. Med. Sci. 145: 399–408, 1976.
 201. Skrabanek, P., AND D. Powell (editors), Substance P. Montreal, Canada: Eden, vol. 1, 1977.
 202. Skrabanek, P., AND D. Powell (editors), Substance P. Montreal, Canada: Eden, vol. 2, 1980.
 203. Skrabanek, P., AND D. Powell (editors), Substance P. Montreal, Canada: Eden, vol. 3, 1983.
 204. Skrabanek, P., AND D. Powell (editors), Substance P‐Dublin 1983. Dublin: Boole, 1983.
 205. Souquet, J.‐C, K. N., Bitar, and G. M. Makhlouf, Binding of radioiodinated substance P and substance K to isolated intestinal smooth muscle cells (Abstract). Gastroenterology 88: 1595, 1985.
 206. Souquet, J.‐C, J. R., Grider, K. N. Bitar, and G. M. Makhlouf, Receptors for mammalian tachykinins on isolated intestinal smooth muscle cells. Am. J. Physiol. 249 (Gastrointest. Liver Physiol. 12): G533–G538, 1985.
 207. Streb, H., R. F., Irvine, M. J. Berridge, and I. Schultz, Release of Ca++ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol 1,4,5‐triphosphate. Nature Lond. 306: 67–69, 1983.
 208. Studer, R. O., H., Trzeciak, and W. Lergier, Isolierung und Aminosäuresequenz von Substanz P aus Pferdedarm. Helv. Chim. Acta 56: 860–866, 1973.
 209. Szeli, J., E., Molina, L. Zappia, and C. Bertaccini, Action of some natural polypeptides on the longitudinal muscle of the guinea‐pig ileum. Eur. J. Pharmacol. 43: 285–287, 1977.
 210. Takano, Y., Y., Takeda, M. Doteuchi, K. Inouye, and H. Kamiya, Effects of a novel tachykinin, substance K, on salivation in rats. Eur. J. Pharmacol. 111: 381–384, 1985.
 211. Tanaka, C., and K. Taniyama, Substance P provokes γ‐aminobutyric acid release from the myenteric plexus of the guinea‐pig small intestine. J. Physiol. Lond. 362: 319–329, 1985.
 212. Tatemoto, K., J. M., Lundberg, H. Jörnvall, and V. Mutt, Neuropeptide K: isolation, structure and biological activities of a novel brain tachykinin. Biochem. Biophys. Res. Commun. 128: 947–953, 1985.
 213. Teichberg, V. L., S., Cohen, and S. Blumberg, Distinct classes of substance P receptors revealed by a comparison of the activities of substance P and some of its segments. Regul. Pept. 1: 323–333, 1981.
 214. Theodorsson‐Norheim, E., E., Brodin, I. Norheim, and S. Rosell, Antisera raised against eledoisin and kassinin detect immunoreactive material in rat tissue extracts: tissue distribution and chromatographic characterization. Regul. Pept. 9: 229–224, 1984.
 215. Theodorsson‐Norheim, E., I. Norheim, K. Öberg, E. Brodin, J. M. Lundberg, K. Tatemoto, and P. G. Lindgren, Neuropeptide K: a major tachykinin in plasma and tumor tissues from carcinoid patients. Biochem. Biophys. Res. Commun. 131: 77–83, 1985.
 216. Togari, A., T., Kato, and T. Nagatsu, Effect of substance P C‐terminal heptapeptide on amylase release in rat parotid gland. Arch. Oral Biol. 25: 597–600, 1980.
 217. Too, H. P., and M. R. Hanley, Peripheral and central substance P binding sites. In: Brain Receptor Methodologies. Amino Acids, Peptides, Psychoactive Drugs, edited by P. J. Marangos, I. C. Campbell, and R. M. Cohen. Orlando, FL: Academic, 1984, pt. B, p. 151–176.
 218. Torrens, Y., S., Lavielle, G. Chassaing, A. Marquet, J. Glowinski, and J. C. Beaujouan, Neuromedin K, a tool to further distinguish two central tachykinin binding sites. Eur. J. Pharmacol. 102: 381–382, 1984.
 219. Torrens, Y., R., Michelot, J. C. Beaujouan, J. Glowinski, and J. Bockaert, In vivo biosynthesis of 35S‐substance P from [35S]methionine in the rat striatum and its transport to the substantia nigra. J. Neurochem. 38: 1728–1734, 1982.
 220. Vogler, K., W., Haefely, A. Hürlimann, R. O. Studer, W. Lergier, R. Strässle, and K. H. Berneis, A new purification procedure and biological properties of substance P. Ann. NY Acad. Sci. 104: 378–389, 1963.
 221. Watson, S. P., Pharmacological characterization of a substance P antagonist, [D‐Arg1,D‐Pro2,D‐Trp79,Leu11]‐substance P. Br. J. Pharmacol. 80: 205–209, 1983.
 222. Watson, S. P., Rapid degradation of [3H]substance P in guinea‐pig ileum and rat vas deferens in vitro. Br. J. Pharmacol. 79: 543–552, 1983.
 223. Watson, S. P., The action of substance P on contraction, inositol phospholipids and adenylate cyclase in rat small intestine. Biochem. Pharmacol. 33: 3733–3737, 1984.
 224. Watson, S. P., and C. P. Downes, Substance P induces hydrolysis of inositol phospholipids in guinea‐pig ileum and rat hypothalamus. Eur. J. Pharmacol. 93: 245–253, 1983.
 225. Watson, S. P., and L. L. Iversen, 3H‐Substance P binding to guinea‐pig ileum longitudinal smooth muscle membranes. Regul. Pept. 8: 273–281, 1984.
 226. Watson, S. P., B. E. B., Sandberg, M. R. Hanley, and L. L. Iversen, Tissue selectivity of substance P alkyl esters: suggesting multiple receptors. Eur. J. Pharmacol. 87: 77–84, 1983.
 227. Yanaihara, C., H., Sato, K. Yanaihara, and K. Abe, Distribution of substance P‐, somatostatin‐, motilin‐, and VIP‐like immunoreactivities in porcine, human, canine, monkey, and tupaia tissues. Proc. Symp. Chem. Physiol. Pathol. 17: 21–26, 1978.
 228. Yasuhara, T., T., Nakajima, G. Falconieri Erspamer, and V. Erspamer, New tachykinins, Glu2,Pro5‐kassinin (Hylambates‐kassinin) and hylambatin, in the skin of the African rhacophorid frog Hylambates maculatus. Biomed. Res. 2: 613–617, 1981.
 229. Yau, W. M., Effect of substance P on intestinal muscle. Gastroenterology 74: 228–231, 1978.
 230. Yau, W. M., and M. L. Youther, Direct evidence for a release of acetylcholine from the myenteric plexus of guinea‐pig small intestine by substance P. Eur. J. Pharmacol. 81: 665–668, 1982.
 231. Zetler, G., New pharmacologically active polypeptides present in impure preparations of substance P. Ann. NY Acad. Sci. 104: 416–436, 1963.
 232. Zuber, H., Isolation of substance P from bovine brain. Ann. NY Acad. Sci. 104: 391–392, 1963.
References in Addendum
 1. Bergström, L., J. C., Beaujouan, Y. Torrens, M. Saffroy, J. Glowinski, S. Lavielle, G. Chaissaing, A. Marquet, P. D'Orleans‐Juste, S. Dion, and D. Regoli, 3H‐neurokinin A labels a specific tachykinin‐binding site in the rat duodenal smooth muscle. Mol. Pharmacol. 32: 764–771, 1987.
 2. Conlon, J. M., C. F., Deacon, L. O'Toole, and L. Thim, Scyliorhinin I and II: two novel tachykinins from dogfish gut. FEBS Lett. 200: 111–116, 1986.
 3. Deacon, C. F., D. V., Agoston, R. Nau, and J. M. Conlon, Conversion of neuropeptide K to neurokinin A and vesicular colocalization of neurokinin A and substance P in neurons of the guinea pig small intestine. J. Neurochem. 48: 141–146, 1987.
 4. Håkanson, R., AND F. Sundler (editors), Tachykinin Antagonists. Amsterdam: Elsevier, 1985.
 5. Harada, Y., T., Takahashi, M. Kuno, N. Nakayama, Y. Masu, and S. Nakanishi, Expression of two different tachykinin receptors in Xenopus oocytes by exogenous mRNAs. J. Neurosci. 7: 3265–3273, 1987.
 6. Henry, J. L., R., Couture, A. C. Cuello, G. Pelletier, R. Quirion, AND D. Regoli (editors), Substance P and Neurokinins. New York: Springer‐Verlag, 1987.
 7. Kotani, H., M., Hoshimaru, H. Nawa, and S. Nakanishi, Structure and gene organization of bovine neuromedin K precursor. Proc. Natl. Acad. Sci. USA 83: 7074–7078, 1986.
 8. Krause, J. E., J. M., Chirgwin, M. S. Carter, Z. S. Xu, and A. D. Hershey, Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin A. Proc. Natl. Acad. Sci. USA 84: 881–885, 1987.
 9. Lee, C.‐M., N. J., Campbell, B. J. Williams, and L. L. Iversen, Multiple tachykinin receptors in peripheral tissues and in brain. Eur. J. Pharmacol. 130: 209–217, 1986.
 10. Maggio, J. E., Tachykinins. Annu. Rev. Neurosci. 11: 13–28, 1988.
 11. Mantyh, C. R., T. S., Gates, R. P. Zimmerman, M. L. Welton, E. P. Passaro, S. R. Vigna, J. E. Maggio, L. Kruger, and P. W. Mantyh, Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn's disease. Proc. Natl. Acad. Sci. USA 85: 3235–3239, 1988.
 12. Mantyh, P. W., C. R., Mantyh, T. Gates, S. R. Vigna, and J. E. Maggio, Receptor binding sites for substance P and substance K in the canine gastrointestinal tract and their possible role in inflammatory bowel disease. Neuroscience 25: 817–838, 1988.
 13. Masu, Y., K., Nakayama, H. Tamaki, Y. Harada, M. Kuno, and S. Nakanishi, cDNA cloning of bovine substance‐K receptor through oocyte expression system. Nature Land. 329: 836–838, 1987.
 14. Popper, P., C. R., Mantyh, S. R. Vigna, J. E. Maggio, and P. W. Mantyh, The localization of sensory nerve fibers and receptor binding sites for sensory neuropeptides in canine mesenteric lymph nodes. Peptides Fayetteville 9: 257–268, 1988.
 15. Souquet, J.‐C., K. N., Bitar, J. R. Grider, and G. M. Makhlouf, Receptors for substance P on isolated intestinal smooth muscle cells of the guinea pig. Am. J. Physiol. 253 (Gastrointest. Liver Physiol. 16): G666–G672, 1987.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Gut Tachykinins
 

How to Cite

John E Maggio, Patrick W Mantyh. Gut Tachykinins. Compr Physiol 2011, Supplement 17: Handbook of Physiology, The Gastrointestinal System, Neural and Endocrine Biology: 661-690. First published in print 1989. doi: 10.1002/cphy.cp060227