Nicotinic Regulation of Adrenomedullary Opioid Peptide Synthesis and Secretion: A Model to Study Monoamine Neuropeptide Cotransmission

  • O. Humberto Viveros
  • Christopher D. Unsworth
  • Tomoyuki Kanamatsu
  • Jau-Shyong Hong
  • Emanuel J. DilibertoJr.
Part of the Advances in Behavioral Biology book series (ABBI, volume 31)


The adrenal medulla chromaffin cell synthesizes and stores in various subcellular compartments a number of proteins, peptides, nucleotides, and other small molecules to be secreted by Ca2+-dependent, nicotine receptor-mediated mechanism(s). Of these proteins and peptides, the enkephalins and other proenkephalin-derived opioid peptides are found in all species examined in substantial amounts, where they are costored with the catecholamines in the chromaffin vesicles. Splanchnic nerve stimulation, nicotine, and other secretagogues induce the cosecretion of these opioid peptides with the amines and other soluble components of these vesicles by the process of exocytosis. Regulatory mechanisms triggered by activation of nicotinic receptors, depolarization, and catecholamine depletion that involve cAMP-dependent and -independent mechanisms control the synthesis of enkephalins at the transcriptional, translational, and peptide processing levels. These mechanisms allow for rapid recovery of the opioid peptide content after secretion and for long-term modulation of the relative proportions and amounts in which catecholamines and enkephalins are costored and cosecreted. Opioid peptides secreted from the adrenal medulla reach ubiquitous opiate receptors throughout the organism and may modulate a number of important systemic functions including behavioral responses to stress. Enkephalins and norepinephrine also coexist in postganglionic sympathetic neurons, and some of the effects of nicotine administration may result from peripheral opiatergic responses through its powerful activation of the sympathetic system. The costorage and cosecretion of opioid peptides and catecholamines is only one of a growing number of examples of coexistence of multiple chemical messengers in single neurons or endocrine cells. This new principle of cotransmission is drastically changing our concepts and understanding of synaptic and endocrine function. Fast and slow dynamic changes in the ratios in which cotransmitters are stored and released and, thus, coact at the effector sites illustrate an unsuspected degree of synaptic plasticity. The exploration of the short-and long-term effects of chronic use of tobacco needs to take into consideration not only the effect of nicotine on classical transmitters but particularly how the biochemistry and function of these central and peripheral cotransmitter systems are being modified.


Chromaffin Cell Nicotinic Receptor Adrenal Medulla Opioid Peptide Adrenal Chromaffin Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hökfelt, T, Johansson, O, Ljungdahl, Å, Lundberg, JM and Schultzberg, M: Peptidergic neurones. Nature (Lond.) 284:515–521, 1980.CrossRefGoogle Scholar
  2. 2.
    Viveros, OH and Wilson, SP: The adrenal chromaffin cell as a model to study the co-secretion of enkephalins and catecholamines. J. Auton. Nery. Syst. 7:41–58, 1983.CrossRefGoogle Scholar
  3. 3.
    Cuello, AC (ed.): Co-transmission, MacMillan, London, 1982.Google Scholar
  4. 4.
    Chan-Palay, V and Palay, SL (eds.): Coexistence of Neuroactive Substances in Neurons, John Wiley &Sons, New York, 1984.Google Scholar
  5. 5.
    Winkler, H and Westhead, E: The molecular organization of adrenal chromaffin granules. Neuroscience 5:1803–1823, 1980.PubMedCrossRefGoogle Scholar
  6. 6.
    Schultzberg, M, Lundberg, JM, Hökfelt, T, Terenius, L, Brandt, J, Elde, RP and Goldstein, M: Enkephalin-like immunoreactivity in gland cells and nerve terminals of the adrenal medulla. Neuroscience 3:1169–1186, 1978.PubMedCrossRefGoogle Scholar
  7. 7.
    Viveros, OH, Diliberto, EJ, Jr., Hazum, E and Chang, K-J: Opiate-like materials in the adrenal medulla: evidence for storage and secretion with catecholamines. Mol. Pharmacol. 16:1101–1108, 1979.PubMedGoogle Scholar
  8. 8.
    Yang, H-YT, Hexum, T and Costa, E: Opioid peptides in adrenal gland. Life Sci. 27:1119–1125, 1980.PubMedCrossRefGoogle Scholar
  9. 9.
    Unsworth, CD and Viveros, OH: Neuropeptides of the adrenal medulla. In (ed.) Rosenheck, K, Stimulus-Secretion Coupling in Chromaffin Cells, CRC Press (in press).Google Scholar
  10. 10.
    Noda, M, Furutani, Y, Takahashi, H, Toyosato, M, Hirose, T, Inayama, S, Nakanishi, S and Numa, S: Cloning and sequence analysis of cDNA for bovine adrenal preproenkephalin. Nature (Lond.) 295:202–206, 1982.CrossRefGoogle Scholar
  11. 11.
    Gubler, U, Seeburg, P, Hoffman, BJ, Gage, LP and Udenfriend, S: Molecular cloning establishes proenkephalin as precursor of enkephalin-containing peptides. Nature (Lond.) 295:206–208, 1982.CrossRefGoogle Scholar
  12. 12.
    Comb, M, Seeburg, PH, Adelman, J, Eiden, L and Herbert, E: Primary structure of the human Met-and Leu-enkephalin precursor and its mRNA. Nature (Lond.) 295:663–666, 1982.CrossRefGoogle Scholar
  13. 13.
    Armitage, AK: Effects of nicotine and tobacco smoke on blood pressure and release of catecholamines from the adrenal glands. Brit. J. Pharmacol. 25:515–526, 1965.PubMedGoogle Scholar
  14. 14.
    Viveros, OH, Wilson, SP, Cubeddu, LX and Kirshner, N: Opioid peptides in human adrenal medulla and pheochromocytoma. In (eds.) Ehrenpreis, S and Sicuteri, F, Degradation of Endogenous Opioids: Its Relevance in Human Pathology and Therapy, Raven Press, New York, 1983, pp. 11–24.Google Scholar
  15. 15.
    Wilson, SP, Viveros, OH and Kirshner, N: Relationship between the regulation of enkephalin-containing peptide and dopamine β-hydroxylase levels in cultured adrenal chromaffin cells. J. Neurochem. 45:1363–1370, 1985.PubMedCrossRefGoogle Scholar
  16. 16.
    Varndell, IM, Tapia, FJ, De Mey, J, Rush, RA, Bloom, SR and Polak, J: Electron immunocytochemical localization of enkephalin-like material in catecholamine-containing cells of the carotid body, the adrenal medulla and pheocyromocytomas of man and other mammals. J. Histochem. and Cytochem. 30:682–690, 1982.CrossRefGoogle Scholar
  17. 17.
    Viveros, OH, Diliberto, EJ, Jr., Hazum, E and Chang, K-J: Enkephalins as possible adrenomedullary hormones: storage, secretion, and regulation of synthesis. In (eds.) Costa, E and Trabucchi, M, Neural Peptides and Neuronal Communication, Raven Press, New York, 1980 pp. 191–204.Google Scholar
  18. 18.
    Wilson, SP, Chang, K-J and Viveros, OH: Proportional secretion of opioid peptides and catecholamines from adrenal chromaffin cells in culture. J. Neurosci. 2:1150–1156, 1982.PubMedGoogle Scholar
  19. 19.
    Kilpatrick, DL, Lewis, RV, Stein, S and Udenfriend, S: Release of enkephalins and enkephalin-containing polypeptides from perfused beef adrenal glands. Proc. Natl. Acad. Sci. (U.S.A.) 77:7473–7475, 1980.CrossRefGoogle Scholar
  20. 20.
    Viveros, OH, Arqueros, L, Connett, RJ and Kirshner, N: Mechanism of secretion from the adrenal medulla. IV. The fate of the storage vesicles following insulin and reserpine administration. Mol. Pharmacol. 5:69–82, 1969.PubMedGoogle Scholar
  21. 21.
    Ryder, SW and Eng, J: Radioimmunoassay of leucine-enkephalin-like substance in human and canine plasma. J. Clin. Endocrinol. Metab. 52:367–369, 1981.PubMedCrossRefGoogle Scholar
  22. 22.
    Hexum, TD, Hanbauer, I, Govoni, S, Yang, H-YT and Costa, E: Secretion of enkephalin-like peptides from canine adrenal gland following splanchnic nerve stimulation. Neuropeptides 1:137–142, 1980.CrossRefGoogle Scholar
  23. 23.
    Viveros, OH, Lee, C-L, Abou-Donia, MM, Nixon, JC and Nichol, CA: Biopterin cofactor biosynthesis: Independent regulation of GTP cyclohydrolase in adrenal medulla and cortex. Science 213:349–350, 1981.PubMedCrossRefGoogle Scholar
  24. 24.
    Thoenen, H, Mueller, RA and Axelrod, J: Tran-synaptic induction of adrenal tyrosine hydroxylase. J. Pharmacol. Exp. Therap. 169:249–254, 1969.Google Scholar
  25. 25.
    Kanamatsu, T, Unsworth, CD, Diliberto, EJ, Viveros, OH and Hong, J-S: Insulin-induced hypoglycemia alters the levels of proenkephalin A mRNA and proenkephalin-related peptides. Soc. Neurosci. Abst. 11:563, 1985.Google Scholar
  26. 26.
    Wilson, SP, Abou-Donia, MM, Chang, K-J and Viveros, OH: Reserpine increases opiate-like peptide content and tyrosine hydroxylase activity in adrenal medullary chromaffin cells in culture. Neuroscience 6:71–79, 1981.PubMedCrossRefGoogle Scholar
  27. 27.
    Wilson, SP, Chang, K-J and Viveros, OH: Synthesis of enkephalins by adrenal medullary chromaffin cells: Reserpine increases incorporation of radiolabeled amino acids. Proc. Natl. Acad. Sci. (U.S.A.) 77:4364–4368, 1980.CrossRefGoogle Scholar
  28. 28.
    Abou-Donia, MM, Wilson, SP, Zimmerman, TP, Nichol, CA and Viveros, OH: Regulation of guanosine triphosphate cyclohydrolase and tetrahydrobiopterin levels and the role of the cofactor in tyrosine hydroxylation in primary cultures of adrenomedullary cells. J. Neurochem. 46:1190–1199, 1985.CrossRefGoogle Scholar
  29. 29.
    Wilson, SP, Unsworth, CD and Viveros, OH: Regulation of opioid peptide synthesis and processing in adrenal chromaffin cells by catecholamines and cyclic adenosine 3′:5′-monophosphate. J. Neuroscience 4:2993–3001, 1984.Google Scholar
  30. 30.
    Eiden, LE, Giraud, P, Affolter, H-A, Herbert, E and Hotchkiss, AJ: Alternative modes of enkephalin biosynthesis regulation by reserpine and cyclic AMP in cultured chromaffin cells. Proc. Natl. Acad. Sci. (U.S.A.) 81:3949–3953, 1984.CrossRefGoogle Scholar
  31. 31.
    Moccheti, I, Guidotti, A, Schwartz, JP and Costa, E: Reserpine changes the dynamic state of enkephalin stores in rat striatum and adrenal medulla by different mechanisms. J. Neuroscience 5:3379–3385, 1985.Google Scholar
  32. 32.
    Wilson, JP, Chang, K-J and Viveros, OH: Opioid peptide synthesis in bovine and human adrenal chromaffin cells. Peptides 2 (suppl. l):83–88, 1981.PubMedCrossRefGoogle Scholar
  33. 33.
    Eiden, LE, Giraud, P, Dave, JR, Hotchkiss, AJ and Affolter, H-U: Nicotinic receptor stimulation activates enkephalin release and biosynthesis in adrenal chromaffin cells. Nature (Lond.) 312:661–663, 1984.CrossRefGoogle Scholar
  34. 34.
    Guidotti, A and Costa, E: A role for nicotinic receptors in the regulation of the adenylate cyclase of adrenal medulla. J. Pharmacol. Exp. Therap. 189:665–675, 1974.Google Scholar
  35. 35.
    Siegel, RE, Eiden, LE and Affolter, H-U: Elevated potassium stimulates enkephalin biosynthesis in bovine chromaffin cells. Neuropeptides 6:543–552, 1985.PubMedCrossRefGoogle Scholar
  36. 36.
    Quach, TT, Tang, F, Kageyama, H, Mocchetti, I, Guidotti, A, Meek, JL, Costa, E and Schwartz, JP: Enkephalin biosynthesis in the adrenal medulla, modulation of proenkephalin mRNA content of cultured chromaffin cells by 8-bromo-adenosine 3′,5′-monophosphate. Molec. Pharmacol. 26:255–260, 1984.Google Scholar
  37. 37.
    Viveros, OH, Arqueros, L and Kirshner, N: Mechanism of secretion from the adrenal medulla: VI. Effect of reserpine on the dopamine β-hydroxylase and catecholamine content and on the buoyant density of adrenal storage vesicles. Molec. Pharmacol. 7:434–443, 1971.Google Scholar
  38. 38.
    Viveros, OH, Daniels, AJ and Diliberto, EJ, Jr.: Cosecretion of catecholamines, opioid peptides, ascorbate, and other secretory products from multiple compartments within adrenomedullary chromaffin cells. In (eds.) Chan-Palay, V and Palay, SL, Coexistence of Neuroactive Substances in Neurons, John Wiley &Sons, New York, 1984, pp. 305–323.Google Scholar
  39. 39.
    Viveros, OH, Arqueros, L and Kirshner, N: Quantal secretion from adrenal medulla: All-or-none release of storage vesicle content. Science 165:911–913, 1969.PubMedCrossRefGoogle Scholar
  40. 40.
    Lewis, JW, Tordoff, MG, Sherman, JE and Liebeskind, JC: Adrenal medullary enkephalin-like peptides may mediate opioid stress analgesia. Science 217:557–559, 1982.PubMedCrossRefGoogle Scholar
  41. 41.
    Lewis, JW, Tordoff, JC, Liebeskind, JC and Viveros, OH: Evidence for adrenal medullary opioid involvement in stress analgesia. Soc. Neurosci. Abstr. 8:778, 1982.Google Scholar
  42. 42.
    Abrahams, VC, Koelle, GB and Smart, P: Histochemical demonstration of cholinesterases in the hypothalamus of the dog. J. Physiol. (Lond.) 139:137–144, 1957.Google Scholar
  43. 43.
    Daniels, AJ, Dean, G, Viveros, OH and Diliberto, EJ, Jr.: Secretion of newly taken up ascorbic acid by adrenomedullary chromaffin cells originates from a compartment different from the catecholamine storage vesicle. Molec. Pharmacol. 23:437–444, 1983.Google Scholar
  44. 44.
    Viveros, OH, Diliberto, EJ, Jr. and Daniels, AJ: Biochemical and functional evidence for the cosecretion of multiple messengers from single and multiple compartments. Fed. Proc. 42:2923–2928, 1983.PubMedGoogle Scholar
  45. 45.
    Wilson, SP, Klein, RL, Chang, K-J, Gasparis, MS, Viveros, OH and Yang, W-H: Are opioid peptides co-transmitters in noradrenergic vesicles of sympathetic nerves? Nature (Lond.) 288:707–709, 1980.CrossRefGoogle Scholar
  46. 46.
    Klein, RL, Wilson, SP, Dzielak, DJ, Yang, W-H and Viveros, OH: Opioid peptides and noradrenaline co-exist in large dense-cored vesicles from sympathetic nerves. Neuroscience 7:2255–2261, 1982.PubMedCrossRefGoogle Scholar
  47. 47.
    Hook, VYH and Eiden, LE: (Met)enkephalin and carboxypeptidase processing enzyme are co-released from chromaffin cells by cholinergic stimulation. Biochem. Biophys. Res. Comm. 128:563–570, 1985.PubMedCrossRefGoogle Scholar
  48. 48.
    Yoshikawa, K, Hong, J-H and Sabol, SL: Electroconvulsive shock increases preproenkephalin messenger RNA abundance in rat hypothalamus. Proc. Natl. Acad. Sci. (U.S.A.) 82:589–593, 1985.CrossRefGoogle Scholar
  49. 49.
    Kanamatsu, T, Unsworth, CD, Diliberto, EJ, Jr., Viveros, OH and Hong, J-S: Reflex splanchnic nerve stimulation increases levels of proenkephalin A mRNA and proenkephalin A related peptides in the rat adrenal medulla. Proc. Natl. Acad. Sci. (U.S.A.) 83:9245–9249, 1986.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • O. Humberto Viveros
    • 1
  • Christopher D. Unsworth
    • 1
  • Tomoyuki Kanamatsu
    • 2
  • Jau-Shyong Hong
    • 1
  • Emanuel J. DilibertoJr.
    • 1
  1. 1.Department of Medicinal BiochemistryThe Wellcome Research LaboratoriesResearch Triangle ParkUSA
  2. 2.Laboratory of Behavioral and Neurological ToxicologyNational Institute of Environmental Health SciencesResearch Triangle ParkUSA

Personalised recommendations