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

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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.

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References

  • 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 108:1939–1943

    CAS  PubMed  Google Scholar 

  • 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 86:7290–7294

    CAS  PubMed  Google Scholar 

  • Aronin N, Coslovsky R, Leeman SE (1986) Substance P and neurotensin: their roles in the regulation of anterior pituitary function. Annu Rev Physiol 48:537–549

    CAS  PubMed  Google Scholar 

  • 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 180:156–161

    CAS  PubMed  Google Scholar 

  • Bonham AC (1995) Neurotransmitters in the CNS control of breathing. Respir Physiol 101:219–230

    CAS  PubMed  Google Scholar 

  • 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 17:284–290

    CAS  PubMed  Google Scholar 

  • 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 384:429–442

    CAS  PubMed  Google Scholar 

  • 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 152:155–158

    CAS  PubMed  Google Scholar 

  • 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 102:281–290

    CAS  PubMed  Google Scholar 

  • 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 13:843–846

    CAS  PubMed  Google Scholar 

  • Dudas B (2017) Central regulation of growth, 1st edn. NOVA Biomedical, New York

    Google Scholar 

  • Dudas B, Merchenthaler I (2002) Close juxtapositions between LHRH immunoreactive neurons and substance P immunoreactive axons in the human diencephalon. J Clin Endocrinol Metab 87:2946–2953

    CAS  PubMed  Google Scholar 

  • 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 18:79–95

    CAS  PubMed  Google Scholar 

  • 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 173–190

    Google Scholar 

  • Ebner K, Singewald N (2006) The role of substance P in stress and anxiety responses. Amino Acids 31:251–272

    CAS  PubMed  Google Scholar 

  • 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 31:338–342

    CAS  PubMed  Google Scholar 

  • Hesketh PJ (2001) Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting. Support Care Cancer 9:350–354

    CAS  PubMed  Google Scholar 

  • 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):1013–1015

    CAS  PubMed  Google Scholar 

  • 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 14:109–115

    CAS  PubMed  Google Scholar 

  • 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 112:147–162

    CAS  PubMed  Google Scholar 

  • 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):397–400

    CAS  PubMed  Google Scholar 

  • 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 35:60–64

    CAS  PubMed  Google Scholar 

  • Magoul R, Onteniente B, Benjelloun W, Tramu G (1993) Tachykinergic afferents to the rat arcuate nucleus. A combined immunohistochemical and retrograde tracing study. Peptides 14:275–286

    CAS  PubMed  Google Scholar 

  • Mantyh PW (2002) Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 63(Suppl 11):6–10

    CAS  PubMed  Google Scholar 

  • 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 17:243–246

    CAS  PubMed  Google Scholar 

  • 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 50:100–108

    CAS  PubMed  Google Scholar 

  • 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 201:167–180

    PubMed  Google Scholar 

  • 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 107:593–599

    CAS  PubMed  Google Scholar 

  • Pisera D, Candolfi M, De Laurentiis A, Seilicovich A (2003) Characterization of tachykinin NK2 receptor in the anterior pituitary gland. Life Sci 73(19):2421–2432

    CAS  PubMed  Google Scholar 

  • 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 297:205–210

    CAS  PubMed  Google Scholar 

  • 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 98:1912–1917

    CAS  PubMed  Google Scholar 

  • Schrauwen E, Houvenaghel A (1980) Substance P: a powerful intestinal vasodilator in the pig. Pflugers Arch 386:281–284

    CAS  PubMed  Google Scholar 

  • 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 32:647–649

    CAS  PubMed  Google Scholar 

  • Skinner DC, Lang AL, Pahl L, Wang Q (2009) Substance P-immunoreactive cells in the ovine pars tuberalis. Neuroendocrinology 89(1):3–8

    CAS  PubMed  Google Scholar 

  • Thornton E, Vink R (2015) Substance P and its tachykinin NK1 receptor: a novel neuroprotective target for Parkinson’s disease. Neural Regen. Res. 10:1403–1405

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tooney PA, Au GG, Chahl LA (2000a) Localisation of tachykinin NK1 and NK3 receptors in the human prefrontal and visual cortex. Neurosci Lett 283:185–188

    CAS  PubMed  Google Scholar 

  • Tooney PA, Au GG, Chahl LA (2000b) Tachykinin NK1 and NK3 receptors in the prefrontal cortex of the human brain. Clin Exp Pharmacol Physiol 27:947–949

    CAS  PubMed  Google Scholar 

  • 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):2079–2085

    CAS  PubMed  Google Scholar 

  • Vijayan E, McCann SM (1980) Effects of substance P and neurotensin on growth hormone and thyrotropin release in vivo and in vitro. Life Sci 26:321–327

    CAS  PubMed  Google Scholar 

  • von Euler US, Gaddum JH (1931) An unidentified depressor substance in certain tissue extracts. J. Physiol 72:74–87

    Google Scholar 

  • 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):612–615

    CAS  PubMed  Google Scholar 

  • 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 33:71–78

    CAS  PubMed  Google Scholar 

  • Zubrzycka M, Janecka A (2000) Substance P: transmitter of nociception (Minireview). Endocr Regul 34:195–201

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Neuroendocrine Organization Laboratory (NEO), Lake Erie College of Osteopathic Medicine (LECOM), 1858 West Grandview Blvd, Erie, PA, 16509, USA

    Andrew Luu, Zachary Oberdoerster, George Grignol & Bertalan Dudas

  2. Department of Epidemiology and Public Health and Anatomy and Neurobiology, University of Maryland Baltimore, 10 South Pine Street Mstf 977, Baltimore, MD, 21201, USA

    Istvan Merchenthaler

Authors
  1. Andrew Luu
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  2. Zachary Oberdoerster
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  3. George Grignol
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  4. Istvan Merchenthaler
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  5. Bertalan Dudas
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Correspondence to Istvan Merchenthaler.

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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.

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Luu, A., Oberdoerster, Z., Grignol, G. et al. Presence of substance P positive terminals on hypothalamic somatostatinergic neurons in humans: the possible morphological substrate of the substance P-modulated growth hormone secretion. Brain Struct Funct 225, 241–248 (2020). https://doi.org/10.1007/s00429-019-01990-x

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  • DOI: https://doi.org/10.1007/s00429-019-01990-x

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