Skip to main content
SpringerLink
Log in

Coexisting peptides in hypothalamic neuroendocrine systems: Some functional implications

  • Review
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Summary

  1. 1.

    Coexisting with oxytocin or vasopressin in the cell bodies and nerve terminals of the hypothalamic-neurohypophysial system are smaller amounts of other peptides. For a number of these “copeptides” there is strong evidence of corelease with the major magnocellular hormones. Guided by the location of their specific receptors we have studied the effects of three copeptides, dynorphin, cholecystokinin (CCK), and corticotropin releasing hormone (CRH), on the secretion of oxytocin and vasopressin from isolated rat neural lobe or neurointermediate lobe preparationsin vitro.

  2. 2.

    Dynorphin is coreleased with vasopression from neural lobe nerve terminals and acts on neural lobe kappa-opiate receptors to inhibit the electrically stimulated secretion of oxytocin. Naloxone augments oxytocin release from the neural lobe in a manner directly proportional to the amount of vasopressin (and presumably dynorphin) released.

  3. 3.

    Cholecystokinin, coreleased with oxytocin by neural lobe terminals, has been shown to have high-affinity receptors located in the NL and to stimulate secretion of both oxytocin and vasopressin. CCK's secretagogue effect was independent of electrical stimulation and extracellular Ca2+ and was blocked by an inhibitor of protein kinase C.

  4. 4.

    CRH, coreleased with OT from the neural lobe, has receptors in the intermediate lobe of the pituitary, but not in the neural lobe itself. CRH stimulates the secretion of oxytocin and vasopressin from combined neurointermediate lobes but not from isolated neural lobes. Intermediate lobe peptides, alpha and gamma melanocyte stimulating hormone, induced secretion of oxytocin and vasopressin from isolated neural lobes. Their effect was, like that of CCK, independent of electrical stimulation and extracellular Ca2+ and blocked by an inhibitor of protein kinase C.

  5. 5.

    Among the CRH-producing parvocellular neurons of the paraventricular nucleus, in the normal rat, approximately half also produce and store vasopressin. After removal of glucocorticoid influence by adrenalectomy, virtually all of the CRH neurons contain vasopressin.

  6. 6.

    The two subtypes of CRH neurosecretory cells found in the normal rat possess different topographical distributions in the paraventricular nucleus, suggesting the possibility of differential innervation. Stress selectively activates the vasopression containing subpopulation of CRH neurons, indicating that there are separate channels of regulatory input controlling the two components of the parvocellular CRH neurosecretory system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Abou-Samra, A.-B., Catt, K. J., and Aguilera, G. (1986). Biphasic inhibition of adrenocorticotropin release by corticosterone in cultured anterior pituitary cells.Endocrinology 119972–977.

    Google Scholar 

  • Alexander, S. L., Irvine, C. H. G., Livesy, J. H., and Donald, R. A. (1988). Effect of isolation stress on concentrations of arginine vasopressin,α-melanocyte-stimulating hormone and ACTH in the pituitary venous effluent of the normal horse.J. Endocrinol. 116325–334.

    Google Scholar 

  • Antoni, F. A. (1986). Hypothalamic control of adrenocorticotropin secretion: Advances since the discovery of 41-residue corticotropin-releasing factor.Endocrine Rev. 7351–378.

    Google Scholar 

  • Antoni, F. A., and Linton, E. A. (1989). Immunocytochemical detection of corticotropin-releasing factor: multiple cross-reactions of a widely used carboxy-terminally directed corticotropinreleasing factor antiserum (code rC70) in rat hypothalamus.Neuroscience 29167–174.

    Google Scholar 

  • Bartfai, T., Iverfeldt, K., Fisone, G., and Serfozo, P. (1988). Regulation of the release of coexisting neurotransmitters.Ann. Rev. Pharmacol. Toxicol. 28285–310.

    Google Scholar 

  • Berkenbosch, F., and Tilders, F. J. H. (1988). Effect of axonal transport blockade on corticotropin releasing factor immunoreactivity in the median eminence of intact and adrenalectommized rats: Relationship between depletion rate and secretory activity.Brain Res. 442312–320.

    Google Scholar 

  • Bicknell, R. J., and Leng, G. (1982). Endogenous opiates regulate oxytocin but not vasopressin secretion from the neurohypophysis.Nature 298161–164.

    Google Scholar 

  • Bicknell, R. J., Ingram, C. D., and Leng, G. (1983). Oxytocin release is inhibited by opiates from the neural lobe, not those from the intermediate lobe.Neurosci. Lett. 43227–230.

    Google Scholar 

  • Bicknell, R. J., Chapman, C., and Leng, G. (1985). Effects of opioid agonists and antagonists on oxytocin and vasopressin release in vitro.Neuroendocrinol 41142–148.

    Google Scholar 

  • Bilezikjian, L. M., Blount, A. L., and Vale, W. W. (1987). The cellular actions of vasopressin on corticotrophs of the anterior pituitary: Resistance to glucocorticoid action.Mol. Endocrinol. 1451–458.

    Google Scholar 

  • Bondy, C. A., and Gainer, H. (1989). Corticotropin-releasing hormone stimulates neurohypophysial hormone release through an interaction with the intermediate lobe of the pituitary.J. Neuroendocrinol 15–8.

    Google Scholar 

  • Bondy, C. A., Gainer, H., and Russell, J. T. (1988). Dynorphin A inhibits and naloxone increases the electrically stimulated release of oxytocin but not vasopressin from the terminals of the neural lobe.Endocrinology 1221321–1327.

    Google Scholar 

  • Bondy, C. A., Gainer, H., Jensen, R. T., and Brady, L. A. (1989). CCK evokes secretion of oxytocin and vasopressin from rat neural lobe independent of external calcium.Proc. Natl. Acad. Sci. 865198–5201.

    Google Scholar 

  • Brady, L. S., Rothman, R. B., and Herkanham, M. (1988). Physiological regulation of neurohypophysial kappa opiate receptor.Brain Res. 443398–402.

    Google Scholar 

  • Brain, S. D., and Williams, T. J. (1988). Substance P regulates the vasodilatory activity of calcitonin gene-related peptide.Nature 33573–75.

    Google Scholar 

  • Brownstein, M. J., and Mezey, E. (1986). Multiple chemical messengers in hypothalamic magnocellular neurons.Prog. Brain Res. 68161–168.

    Google Scholar 

  • Bunn, S. J., Hanley, M. R., and Wilkin, G. P. (1985). Evidence for a kappa opioid receptor on pituitary astrocytes: An autoradiographic study.Neurosci Lett. 55317–323.

    Google Scholar 

  • Burlet, A., Tonon, M.-C., Tankosic, P., Coy, D., and Vaudry, H. (1983). Comparative immunocytochemical localization of corticotropin-releasing factor (CRF-41) and neurohypophysial peptides in the brain of Brattleboro and Long Evans rats.Neuroendocrinology 3764–72.

    Google Scholar 

  • Campbell, G. (1987). Cotransmission.Annu. Rev. Pharmacol. Toxicol. 2751–70.

    Google Scholar 

  • Carter, D. A., and Lightman, S. L. (1987). Temporal changes in the activity of endogenous opioid mechanisms regulating oxytocin secretion in saline loaded rats.Neurosci. Lett. 82191–195.

    Google Scholar 

  • Clarke, G., Wood, P., Merrick, L., and Lincoln, D. W. (1979). Opiate inhibition of peptide release from neurohumoral terminals of hypothalamic neurons.Nature 282746–749.

    Google Scholar 

  • Dallman, M. F., Akana, S. F., Jacobson, L., Levin, N., Cascio, C. S., and Shinsako, J. (1987). Characterization of corticosterone feedback regulation of ACTH secretion.Ann. N.Y. Acad. Sci. 512402–414.

    Google Scholar 

  • Deschepper, C., Lotstra, F., Vandesande, F., and Vanderhaeghen, J. J. (1983). Cholecystokinin varies in the posterior pituitary and external median eminence of the rat according to factors affecting vasopressin and oxytocin.Life Sci. 322571–2577.

    Google Scholar 

  • De Souza, E. B., and Kuhar, M. J. (1986). Corticotropin-releasing factor receptors in the pituitary gland and central nervous system.Methods Enzymol. 124560–589.

    Google Scholar 

  • Dreyfuss, F., Burlet, A., Tonon, M. C., and Vaudry, H. (1984). Comparative immunoelectron microscopic localization of corticotropin-releasing factor (CRF-41) and oxytocin in the rat median eminence.Neuroendocrinology 39284–287.

    Google Scholar 

  • Falke, N. (1988). Dynorphin (1-8) inhibits stimulated release of oxytocin but not vasopressin from isolated neurosecretory endings of the rat neurohypophysis.Neuropeptides 11163–167.

    Google Scholar 

  • Falke, N., and Martin, R. (1985). Opioid binding in a rat neurohypophysial fraction enriched in secretory nerve endings.Neurosci. Lett. 6137–41.

    Google Scholar 

  • Falke, N., and Martin, R. (1988). Opiate binding differentially associated with oxytocin and vasopressin nerve endings from porcine neurohypophysis.Exp. Brain Res. 70145–154.

    Google Scholar 

  • Gardner, J. D., and Jensen, R. T., (1986). Receptors and cell activation associated with pancreatic enzyme secretion.Annu. Rev. Physiol. 48103–117.

    Google Scholar 

  • Gaymann, W., and Martin, R. (1987). A re-examination of the localization of immunoreactive dynorphin 1-8, leu-enkephalin and met-enkephalin in the rat neurohypophysis.Neuroscience 201069–1080.

    Google Scholar 

  • Gerstenberger, R., and Barden, N. (1986). Dynorphin 1-8 binds to opiate kappa receptors in the neurohypophysis.Neuroendocrinology 42379–379.

    Google Scholar 

  • Gillies, G., and Lowry, P. (1979). Corticotrophin releasing factor may be modulated by vasopressin.Nature 278463–464.

    Google Scholar 

  • Hartman, R. D., Rosella-Dampman, L. M., Emmert, S. E., and Summy-Long, J. Y. (1986). Ontogeny of opioid inhibition of vasopressin and oxytocin release in response to osmotic stimulation.Endocrinology 1191–11.

    Google Scholar 

  • Hauger, R. L., Millan, M. A., Lorang, M., Harwood, J. P., and Aguilera, G. (1988). Corticotropinreleasing factor receptors and pituitary adrenal responses during immobilization stress.Endocrinology 123396–405.

    Google Scholar 

  • Herkenham, M., Rice, K. C., Jacobson, A. E., and Rothman, R. B. (1986). Opiate receptors in rat pituitary are confined to the neural lobe and are exclusively kappa.Brain Res. 382365–371.

    Google Scholar 

  • Hökfelt, T., Fuxe, K., and Pernow, B. (Eds.) (1986). Coexistence of neuronal messengers: A new principle in chemical transmission.Prog. Brain Res. 68:1-411.

    Google Scholar 

  • Hökfelt, T., Fahrenkrug, J., Ju, G., Ceccatelli, S., Tsuruo, Y., Meister, B., Mutt, V., Rundgren, M., Brodin, E., Terenius, L., Hulting, A.-L., Werner, S., Björklund, H., and Vale, W. (1987). Analysis of peptide histidine-isoleucine/vasoactive intenstinal polypeptide-immunoreactive neurons in the central nervous system with special reference to their relation to corticotropin releasing factor- and enkephalin-like immunoreactivities in the paraventricular hypothalamic nucleus.Neuroscience 23827–857.

    Google Scholar 

  • Keller-Wood, M. E., and Dallman, M. F. (1984). Corticosteroid inhibition of ACTH secretion.Endocrine Rev. 51–24.

    Google Scholar 

  • Kiss, J. Z., Mezey, E., and Skirboll, L. (1984). Corticotropin-releasing factor-immunoreactive neurons of the paraventricular nucleus become vasopressin-positive after adrenalectomy.Proc. Natl. Acad. Sci. USA 811854–1858.

    Google Scholar 

  • Lightman, S. L., and Young, W. S. (1987). Vasopressin, oxytocin, dynorphin, enkephalin and corticotropin releasing factor mRNA during osmotic stimulation in the rat.J. Physiol. (London)39423–39.

    Google Scholar 

  • Lightman, S. L., Ninkovic, M., Hunt, S. P., and Iverson, L. L. (1983). Evidence for opiate receptors on pituicytes.Nature 305235–237.

    Google Scholar 

  • Lincoln, D. W., and Russell, I. R. (1985). Oxytocin and vasopressin secretion: New perspectives. InNeuroendocrine Molecular Biology (G. Fink, A. J. Harmer, and K. W. McKerns, Eds.), Plenum, New York.

    Google Scholar 

  • Lundberg, J. M., and Hökfelt, T. (1986). Multiple co-existence of peptides and classical transmitters in peripheral autonomic and sensory neurons—functional and pharmacological implications.Prog. Brain Res. 68241–262.

    Google Scholar 

  • MacDonald, R. A., and Werz, M. A. (1986). Dynorphin A decreases voltage dependent calcium conductance of mouse dorsal root ganglion neurons.J. Physiol. (London)377237–245.

    Google Scholar 

  • Marley, P. D., Lightman, S. L., Forsling, M. L., Todd, K., Goedert, M., Rehfeld, J. F., and Emson, P. C. (1984). Localization and actions of cholecystokinin in the rat pituitary intermediate lobe.Endocrinology 1141902–1911.

    Google Scholar 

  • Martin, R., Geis, R., Holl, R., Schafer, M., and Voight, K. H. (1983). Coexistence of unrelated peptides in oxytocin and vasopressin terminals of rat neurohypophyses: Immunoreactive methionine-enkephalin-, leucine-enkephalin- and cholecystokinin-like substances.Neuroscience 8213–227.

    Google Scholar 

  • Mendelsohn, F. A. O., Aguilera, G., Saavedra, J. M., Quirion, R., and Catt, K. J. (1983). Characteristics and regulation of angiotensin II receptors in pituitary, circumventricular organ and kidney.Clin. Exp. Hypertens. A51081–1097.

    Google Scholar 

  • Meunier, H., Fefevre, G., Dumont, D., and Labrie, F. (1982). CRF stimulates a-MSH secretion and cyclic AMP accumulation in rat pars intermedia cells.Life Sci. 312129–2135.

    Google Scholar 

  • Millan, M., Aguilera, G., Wynn, P. C., Mendelsohn, F. A. O., and Catt, K. J. (1986). Autoradiographic localization of brain receptors for peptide hormones: Angiotensin II, corticotropin-releasing factor and gonadotropin-releasing hormone,Methods Enzymol. 124590–606.

    Google Scholar 

  • Miller, R. F. (1988). Are single retinal neurons both excitatory and inhibitory?Nature 336517–518.

    Google Scholar 

  • Mulle, C., Benoit, P., Pinset, C., Roa, M., and Changeux, J.-P. (1988). Calcitonin gene-related peptide enhances the rate of desensitization of the nicotinic acetylcholine receptor in cultured mouse muscle cells.Proc. Natl. Acad. Sci. 85 5728–6732.

    Google Scholar 

  • Munemura, M., Eskay, R. L., and Kebabian, J. W. (1980). Release of a-MSH from dispersed cells of the intermediate lobe of the rat pituitary gland.Endocrinology 1061795–1799.

    Google Scholar 

  • New, H. V., and Mudge, A. W. (1986). Calitonin gene-related peptide regulates muscle acetycholine receptor synthesis.Nature 323809–811.

    Google Scholar 

  • Nordmann, J. J., Dayanithi, G., and Cazalis, M. (1986). Do opioid peptides modulate, at the level of nerve endings, the release of neurohypophysial hormones?Exp. Brain Res. 61560–566.

    Google Scholar 

  • North, R. A. (1986). Opioid receptor types and membrane ion channels.Trends Neurosci. March:114–117.

    Google Scholar 

  • Palkovits, M., Kiss, J. Z., Beinfeld, M. C., and Brownstein, M. J. (1984). Cholecystokinin in the hypothalamo-hypophysial system.Brain Res. 299186–189.

    Google Scholar 

  • Pesce, G., Lang, M. A., Russell, J. T., Rodbard, D., and Gainer, H. (1987). Characterization of kappa opioid receptors in neurosecretosomes from bovine posterior pituitary.J. Neurochem. 49421.

    Google Scholar 

  • Plotsky, P. M. (1987). Regulation of hypophysiotropic factors mediating ACTH secretion.Ann. N. Y. Acad. Sci. 512205–217.

    Google Scholar 

  • Saavedra, J. M., Rougeot, C., Culman, J., Israel, A., Niwa, M., Tonon, M. C., Vaudry, H., and Dray, F. (1984). Decreased corticotropin-releasing factor-like immunoreactivity in rat intermediate and posterior pituitary after stalk section.Neuroendocrinol. 3993–95.

    Google Scholar 

  • Saland, L. C., Gutierrez, L., Kraner, J., and Samora, A. (1988). Corticotropin-releasing factor and neurotransmitters modulate melanotropic peptide release from rat neurointermediate pituitary in vitro.Neuropeptides 1259–66.

    Google Scholar 

  • Sawchenko, P. E., Swanson, L. W., and Vale, W. (1984a). Co-expression of corticotropin-releasing factor and vasopressin immunoreactivity in parvocellular neurosecretory neurons of the adrenalectomized rat.Proc. Natl. Acad. Sci. USA 811883–1887.

    Google Scholar 

  • Sawchenko, P. E., Swanson, L. W., and Vale, W. W. (1984b). Corticotropin-releasing factor: Coexpression within distinct subsets of oxytocin-, vasopressin-, and neurotensin-immunoreactive neurons in the hypothalamus of the male rat.J. Neurosci. 41118–1129.

    Google Scholar 

  • Schwartz, J., and Vale, W. (1988). Dissociation of the adrenocorticotropin secretory responses to corticotropin-releasing factor (CRF) and vasopressin or oxytocin by using a specific cytotoxic analog of CRF.Endrocrinology 1221695–1700.

    Google Scholar 

  • Sherman, T. G., Day, R., Civelli, O., Douglass, J., Herbert, E., Akil, H., and Watson, S. J. (1988). The regulation of hypothalamic magnocellular neuropeptides and their mRNAs in the Brattleboro rat: Coordinate responses to further osmotic challege.J. Neurosci. 83797–3811.

    Google Scholar 

  • Stillman, M. A., Recht, L. D., Rosario, S. L., Seif, S. M., Robinson, A. G., and Zimmerman, E. A. (1977). The effects of adrenalectomy and glucocorticoid replacement on vasopressin and vasopressin-neurophysin in the zona externa of the rat.Endocrinology 10142–49.

    Google Scholar 

  • Stoeckel, M. E., Schmitt, G., and Porte, A. (1981). Fine structure and cytochemistry of the mammalian pars intermedia. In (D. Everad and G. Lawrenson, Eds.)Peptides of the Pars Intermedia, CIBA Foundation Symposium 81 Pittman Medical, London, pp. 101–127.

    Google Scholar 

  • Summy-Long, J. Y., Miller, D. S., Rosella-Dampman, L. M., Hartman, R. D., and Emmert, S. E. (1984). A functional role for opioid peptides in the differential secretion of vasopressin and oxytocin.Brain Res. 309362–366.

    Google Scholar 

  • Tramu, G., Croix, C., and Pillez, A. (1983). Ability of the CRF immunoreactive neurons of the paraventricular nucleus to produce a vasopressin-like material.Neuroendocrinology 37467–469.

    Google Scholar 

  • Tweedle, C. D. (1983). Ultrastructural manifestations of increased hormone release in the neurohypophysis.Prog. Brain Res. 60259–267.

    Google Scholar 

  • Vale, W., Spiess, J., Rivier, C., and Rivier, J. (1981). Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin andβ-endorphin.Science 2131394–1397.

    Google Scholar 

  • Vanderhaeghen, J. J., Lotstra, F., DeMey, J., and Gillies, C. (1980). Immunocytochemical localization of chelecystokinin and gastrin-like peptides in the brain and hypophysis of the rat.Proc. Natl. Acad. Sci. 771194.

    Google Scholar 

  • Verbalis, J. G., McCann, M. J., McHale, C. M., and Stricker, E. M. (1986). Oxytocin secretion in response to cholecystokinin and food: differentiation of nausea from satiety.Science 2321417–1417.

    Google Scholar 

  • Watson, S. J., Akil, H., Fischli, W., Goldstein, A., Zimmerman, E., Nilaver, G., and van Wimersma Greidanus, T. B. (1983). Dynorphin and vasopressin: Common localization in magnocellular neurons.Science 21685–87.

    Google Scholar 

  • Whitnall, M. H. (1988a). Is there a “final common pathway” in the regulation of ACTH release?Adv. Exp. Biol. Med. 36143–156.

    Google Scholar 

  • Whitnall, M. H. (1988b). Distributions of pro-vasopressin expressing and pro-vasopressin deficient CRH neurons in the paraventricular hypothalamic nucleus of colchicine-treated adrenalectomized rats.J. Comp. Neurol. 27513–28.

    Google Scholar 

  • Whitnall, M. H. (1989). Stress selectively activates the vasopressin containing subset of corticotropinreleasing hormone neurons.Neuroendocrinology (in press).

  • Whitnall, M. H., and Gainer, H. (1988). Major pro-vasopressin-expressing and pro-vasopressindeficient subpopulations of corticotropin-releasing hormone neurons in normal rats. Differential distributions within the paraventricular nucleus.Neuroendocrinology 47176–180.

    Google Scholar 

  • Whitnall, M. H., Gainer, H., Cox, B. M., and Molineaux, C. J. (1983). Dynorphin-A-(1-8) is contained within vasopressin neurosecretory granules in rat pituitary.Science 2221137–1139.

    Google Scholar 

  • Whitnall, M. H., Mezey, E., and Gainer, H. (1985). Co-localization of corticotropin-releasing factor and vasopressin in median eminence neurosecretory veiscles.Nature 317248–250.

    Google Scholar 

  • Whitnall, M. H., Smyth, D., and Gainer, H. (1987). Vasopressin coexists in half of the corticotropin-releasing factor axons present in the external zone of the median eminence in normal rats.Neuroendocrinology 45420–424.

    Google Scholar 

  • Wolfson, B., Manning, R. W., Davis, L. G., Arentzen, R., and Baldino, F., Jr. (1985). Colocalization of corticotropin releasing factor and vasopressin mRNA in neurones after adrenalectomy.Nature 31559–61.

    Google Scholar 

  • Zamir, N., Zamir, D., Eiden, L. E., Palkovits, M., Bronstein, M., Eskay, R. L., Weber, E., Faden, A. I., and Feuerstein, G. (1985). Methionine and leucine enkephalin in the rat neurohypophysis: Different respenses to osmotic stimuli and T2 toxic.Science 228606–608.

    Google Scholar 

  • Zhao, B.-G., Chapman, C., and Bicknell, R. J. (1988). Functional Kappa-opioid receptors on oxytocin and vasopressin nerve terminals isolated from the rat neurohypophysis.Brain Res. 46262–66.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 20892, Bethesda, Maryland, USA

    Carolyn A. Bondy, Mark H. Whitnall & Harold Gainer

  2. Unit on Functional Neuroanatomy, National Institue of Mental Health, National Institutes of Health, 20892, Bethesda, Maryland, USA

    Linda S. Brady

Authors
  1. Carolyn A. Bondy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark H. Whitnall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linda S. Brady
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Harold Gainer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bondy, C.A., Whitnall, M.H., Brady, L.S. et al. Coexisting peptides in hypothalamic neuroendocrine systems: Some functional implications. Cell Mol Neurobiol 9, 427–446 (1989). https://doi.org/10.1007/BF00712791

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00712791

Key words

Search

Navigation