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Brain Structure and Function

, Volume 225, Issue 1, pp 241–248 | Cite as

Presence of substance P positive terminals on hypothalamic somatostatinergic neurons in humans: the possible morphological substrate of the substance P-modulated growth hormone secretion

  • Andrew Luu
  • Zachary Oberdoerster
  • George Grignol
  • Istvan MerchenthalerEmail author
  • Bertalan Dudas
Original Article

Abstract

Substance P is an undecapeptide affecting the gastrointestinal, cardiovascular, and urinary systems. In the central nervous system, substance P participates in the regulation of pain, learning, memory, and sexual homeostasis. In addition to these effects, previous papers provided solid evidence that substance P exhibits regulatory effects on growth. Indeed, our previous study revealed that growth hormone-releasing hormone (GHRH) neurons appear to be densely innervated by substance P fibers in humans. Since growth hormone secretion is regulated by the antagonistic actions of both GHRH and somatostatin, in the present paper we have examined the possibility that SP may also affect growth via the somatostatinergic system. Therefore, we have studied the putative presence of juxtapositions between the substance P-immunoreactive (IR) and somatostatinergic systems utilizing double label immunohistochemistry combined with high magnification light microscopy with oil immersion objective. In the present study, we have revealed a dense network of substance P-IR axonal varicosities contacting the majority of somatostatin-IR neurons in the human hypothalamus. Somatostatinergic perikarya are often covered by these fiber varicosities that frequently form basket-like encasements with multiple en passant type contacts, particularly in the infundibular nucleus/median eminence and in the basal periventricular area of the tuberal region. In addition, numerous substance-P-somatostatinergic juxtapositions can be found in the basal perifornical zone of the tuberal area. If these contacts are indeed functional synapses, they may represent the morphological substrate of the control of substance P on growth. Indeed, the frequency and density of these juxtapositions indicate that in addition to the regulatory action of substance P on GHRH secretion, substance P also influences growth by regulating hypothalamic somatostatinergic system via direct synaptic contacts.

Keywords

Substance P Somatostatin Juxtaposition Immunohistochemistry Human hypothalamus 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants

The brain utilized in these studies was harvested 12 h post mortem period in accordance with the regulations of the Institutional Review Board of Lake Erie College of Osteopathic Medicine (LECOM). See materials and methods.

References

  1. Abe H, Chihara K, Chiba T, Matsukura S, Fujita T (1981) Effect of intraventricular injection of neurotensin and other various bioactive peptides on plasma immunoreactive somatostatin levels in rat hypophysial portal blood. Endocrinology 108:1939–1943PubMedGoogle Scholar
  2. Arisawa M, Snyder GD, De PL, Ho RH, Xu RK, Pan G et al (1989) Role of substance P in suppressing growth hormone release in the rat. Proc Natl Acad Sci USA 86:7290–7294PubMedGoogle Scholar
  3. Aronin N, Coslovsky R, Leeman SE (1986) Substance P and neurotensin: their roles in the regulation of anterior pituitary function. Annu Rev Physiol 48:537–549PubMedGoogle Scholar
  4. Bitar KG, Bowers CY, Coy DH (1991) Effect of substance P/bombesin antagonists on the release of growth hormone by GHRP and GHRH. Biochem Biophys Res Commun 180:156–161PubMedGoogle Scholar
  5. Bonham AC (1995) Neurotransmitters in the CNS control of breathing. Respir Physiol 101:219–230PubMedGoogle Scholar
  6. Bossaller C, Reither K, Hehlert-Friedrich C, uch-Schwelk W, Graf K, Grafe M et al (1992) In vivo measurement of endothelium-dependent vasodilation with substance P in man. Herz 17:284–290PubMedGoogle Scholar
  7. Chawla MK, Gutierrez GM, Young WS, McMullen NT, Rance NE (1997) Localization of neurons expressing substance P and neurokinin B gene transcripts in the human hypothalamus and basal forebrain. J Comp Neurol 384:429–442PubMedGoogle Scholar
  8. Cheng K, Wei L, Chaung LY, Chan WW, Butler B, Smith RG (1997) Inhibition of L-692,429-stimulated rat growth hormone release by a weak substance P antagonist: L-756,867. J Endocrinol 152:155–158PubMedGoogle Scholar
  9. Chihara K, Arimura A, Coy DH, Schally AV (1978) Studies on the interaction of endorphins, substance P. and endogenous somatostatin in growth hormone and prolactin release in rats. Endocrinology 102:281–290PubMedGoogle Scholar
  10. Coiro V, Volpi R, Capretti L, Speroni G, Bocchi R, Caffarri G et al (1992) Intravenously infused substance P enhances basal and growth hormone (GH) releasing hormone-stimulated GH secretion in normal men. Peptides 13:843–846PubMedGoogle Scholar
  11. Dudas B (2017) Central regulation of growth, 1st edn. NOVA Biomedical, New YorkGoogle Scholar
  12. Dudas B, Merchenthaler I (2002) Close juxtapositions between LHRH immunoreactive neurons and substance P immunoreactive axons in the human diencephalon. J Clin Endocrinol Metab 87:2946–2953PubMedGoogle Scholar
  13. Dudas B, Merchenthaler I (2006) Three-dimensional representation of the neurotransmitter systems of the human hypothalamus: inputs of the gonadotrophin hormone-releasing hormone neuronal system. J Neuroendocrinol 18:79–95PubMedGoogle Scholar
  14. Dudas B, Peroski MS, Merchenthaler I (2013) Hypothalamic regulation of growth. In: Dudas B (ed) The human hypothalamus: anatomy, functions and disorders. Nova Biomedical, New York, pp 173–190Google Scholar
  15. Ebner K, Singewald N (2006) The role of substance P in stress and anxiety responses. Amino Acids 31:251–272PubMedGoogle Scholar
  16. Eckstein N, Wehrenberg WB, Louis K, Carmel PW, Zimmermann EA, Frantz AG et al (1980) Effects of substance P on anterior pituitary secretion in the female rhesus monkey. Neuroendocrinology 31:338–342PubMedGoogle Scholar
  17. Hesketh PJ (2001) Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting. Support Care Cancer 9:350–354PubMedGoogle Scholar
  18. Hokfelt T, Pernow B, Nilsson G, Wetterberg L, Goldstein M, Jeffcoate SL (1978) Dense plexus of substance P immunoreactive nerve terminals in eminentia medialis of the primate hypothalamus. Proc Natl Acad Sci USA 75(2):1013–1015PubMedGoogle Scholar
  19. Houben H, Denef C (1993) Unexpected effects of peptide and nonpeptide substance P receptor antagonists on basal prolactin and growth hormone release in vitro. Peptides 14:109–115PubMedGoogle Scholar
  20. Huston JP, Hasenohrl RU, Boix F, Gerhardt P, Schwarting RK (1993) Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity. Psychopharmacology 112:147–162PubMedGoogle Scholar
  21. Ju G, Liu S (1989) Relationship of Substance P-lmmunoreactive Nerve Fibers with Somatotropes of the Anterior Pituitary in the Monkey. J Neuroendocrinol 1(6):397–400PubMedGoogle Scholar
  22. Lemamy GJ, Guillaume V, Ndeboko B, Mouecoucou J, Oliver C (2012) Substance P stimulates growth hormone (GH) and GH-releasing hormone (GHRH) secretions through tachykinin NK2 receptors in sheep. Peptides 35:60–64PubMedGoogle Scholar
  23. Magoul R, Onteniente B, Benjelloun W, Tramu G (1993) Tachykinergic afferents to the rat arcuate nucleus. A combined immunohistochemical and retrograde tracing study. Peptides 14:275–286PubMedGoogle Scholar
  24. Mantyh PW (2002) Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 63(Suppl 11):6–10PubMedGoogle Scholar
  25. Meeking DR, Allard S, Munday J, Chowienczyk PJ, Shaw KM, Cummings MH (2000) Comparison of vasodilator effects of substance P in human forearm vessels of normoalbuminuric Type 1 diabetic and non-diabetic subjects. Diabet Med 17:243–246PubMedGoogle Scholar
  26. Mikkelsen JD, Larsen PJ, Moller M, Vilhardt H, Saermark T (1989) Substance p in the median eminence and pituitary of the rat: demonstration of immunoreactive fibers and specific binding sites. Neuroendocrinology 50:100–108PubMedGoogle Scholar
  27. O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin CP, Shanahan F (2004) The role of substance P in inflammatory disease. J Cell Physiol 201:167–180PubMedGoogle Scholar
  28. Park SW, Yan YP, Satriotomo I, Vemuganti R, Dempsey RJ (2007) Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions. J Neurosurg 107:593–599PubMedGoogle Scholar
  29. Pisera D, Candolfi M, De Laurentiis A, Seilicovich A (2003) Characterization of tachykinin NK2 receptor in the anterior pituitary gland. Life Sci 73(19):2421–2432PubMedGoogle Scholar
  30. Proudan N, Peroski M, Grignol G, Merchenthaler I, Dudas B (2015) Juxtapositions between the somatostatinergic and growth hormone-releasing hormone (GHRH) neurons in the human hypothalamus. Neuroscience 297:205–210PubMedGoogle Scholar
  31. Santarelli L, Gobbi G, Debs PC, Sibille ET, Blier P, Hen R et al (2001) Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function. Proc Natl Acad Sci USA 98:1912–1917PubMedGoogle Scholar
  32. Schrauwen E, Houvenaghel A (1980) Substance P: a powerful intestinal vasodilator in the pig. Pflugers Arch 386:281–284PubMedGoogle Scholar
  33. Sheppard MC, Kronheim S, Pimstone BL (1979) Effect of substance P, neurotensin and the enkephalins on somatostatin release from the rat hypothalamus in vitro. J Neurochem 32:647–649PubMedGoogle Scholar
  34. Skinner DC, Lang AL, Pahl L, Wang Q (2009) Substance P-immunoreactive cells in the ovine pars tuberalis. Neuroendocrinology 89(1):3–8PubMedGoogle Scholar
  35. Thornton E, Vink R (2015) Substance P and its tachykinin NK1 receptor: a novel neuroprotective target for Parkinson’s disease. Neural Regen. Res. 10:1403–1405PubMedPubMedCentralGoogle Scholar
  36. Tooney PA, Au GG, Chahl LA (2000a) Localisation of tachykinin NK1 and NK3 receptors in the human prefrontal and visual cortex. Neurosci Lett 283:185–188PubMedGoogle Scholar
  37. Tooney PA, Au GG, Chahl LA (2000b) Tachykinin NK1 and NK3 receptors in the prefrontal cortex of the human brain. Clin Exp Pharmacol Physiol 27:947–949PubMedGoogle Scholar
  38. Uhlman D, Nguyen T, Grignol G, Merchenthaler I, Dudas B (2019) Substance P appears to affect growth via growth hormone-releasing hormone (GHRH) neurons in the human hypothalamus. Brain Struct Funct 224(6):2079–2085PubMedGoogle Scholar
  39. Vijayan E, McCann SM (1980) Effects of substance P and neurotensin on growth hormone and thyrotropin release in vivo and in vitro. Life Sci 26:321–327PubMedGoogle Scholar
  40. von Euler US, Gaddum JH (1931) An unidentified depressor substance in certain tissue extracts. J. Physiol 72:74–87Google Scholar
  41. Wormald PJ, Millar RP, Kerdelhue B (1989) Substance P receptors in human pituitary: a potential inhibitor of luteinizing hormone secretion. J Clin Endocrinol Metab 69(3):612–615PubMedGoogle Scholar
  42. Yamauchi N, Shibasaki T, Ling N, Demura H (1991) In vitro release of growth hormone-releasing factor (GRF) from the hypothalamus: somatostatin inhibits GRF release. Regul Pept 33:71–78PubMedGoogle Scholar
  43. Zubrzycka M, Janecka A (2000) Substance P: transmitter of nociception (Minireview). Endocr Regul 34:195–201PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Andrew Luu
    • 1
  • Zachary Oberdoerster
    • 1
  • George Grignol
    • 1
  • Istvan Merchenthaler
    • 2
    Email author
  • Bertalan Dudas
    • 1
  1. 1.Neuroendocrine Organization Laboratory (NEO)Lake Erie College of Osteopathic Medicine (LECOM)ErieUSA
  2. 2.Department of Epidemiology and Public Health and Anatomy and NeurobiologyUniversity of Maryland BaltimoreBaltimoreUSA

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