Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1986 Dec 1;5(12):3163–3166. doi: 10.1002/j.1460-2075.1986.tb04624.x

Neuronal localization of the neutral endopeptidase 'enkephalinase' in rat brain revealed by lesions and autoradiography.

G Waksman, E Hamel, P Delay-Goyet, B P Roques
PMCID: PMC1167307  PMID: 3545813

Abstract

The cellular localization of rat brain enkephalinase was studied after induction of selective unilateral lesions using in vitro quantitative autoradiography of the specific binding of the enzyme inhibitor [3H]-N-[(2RS)-3-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl]glycine ([3H]HACBO-Gly). Twenty-one days following injection of kainic acid in the caudate-putamen (CP) [3H]HACBO-Gly binding was locally decreased by 52% with a concomitant reduction of 67 and 78% in the ipsilateral substantia nigra (SN) and globus pallidus (GP), respectively. Inhibition of axonal transport in the CP by unilateral stereotaxic injection of colchicine induced a large (30-60%) and progressive decrease in enkephalinase labelling within the ipsilateral GP and SN. Taken together these results strongly suggest that in the CP a large fraction of enkephalinase is localized on intrinsic striatal neurones, and that the enzyme present both in the GP and the SN is partly localized on nerve terminals originating from neurones in the CP. No change in [3H]HACBO-Gly binding was observed in the CP following injection of 6-hydroxydopamine in the nigrostriatal bundle, contrasting with the 30% depletion in opioid receptors. This would indicate that enkephalinase is present in only very low amounts, if at all, on striatal dopaminergic nerve terminals.

Full text

PDF
3163

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abou-Khalil B., Young A. B., Penney J. B. Evidence for the presynaptic localization of opiate binding sites on striatal efferent fibers. Brain Res. 1984 Dec 3;323(1):21–29. doi: 10.1016/0006-8993(84)90261-0. [DOI] [PubMed] [Google Scholar]
  2. Bourgoin S., Le Bars D., Artaud F., Clot A. M., Bouboutou R., Fournie-Zaluski M. C., Roques B. P., Hamon M., Cesselin F. Effects of kelatorphan and other peptidase inhibitors on the in vitro and in vivo release of methionine-enkephalin-like material from the rat spinal cord. J Pharmacol Exp Ther. 1986 Jul;238(1):360–366. [PubMed] [Google Scholar]
  3. Brownstein M. J., Mroz E. A., Tappaz M. L., Leeman S. E. On the origin of substance P and glutamic acid decarboxylase (GAD) in the substantia nigra. Brain Res. 1977 Oct 28;135(2):315–323. doi: 10.1016/0006-8993(77)91034-4. [DOI] [PubMed] [Google Scholar]
  4. Cascieri M. A., Bull H. G., Mumford R. A., Patchett A. A., Thornberry N. A., Liang T. Carboxyl-terminal tripeptidyl hydrolysis of substance P by purified rabbit lung angiotensin-converting enzyme and the potentiation of substance P activity in vivo by captopril and MK-422. Mol Pharmacol. 1984 Mar;25(2):287–293. [PubMed] [Google Scholar]
  5. Chesselet M. F., Cheramy A., Reisine T. D., Lubetzki C., Glowinski J., Fournie-Zaluski M. C., Roques B. Effects of various opiates including specific delta and mu agonists on dopamine release from nigrostriatal dopaminergic neurons in vitro in the rat and in vivo in the cat. Life Sci. 1982 Nov 15;31(20-21):2291–2294. doi: 10.1016/0024-3205(82)90140-0. [DOI] [PubMed] [Google Scholar]
  6. Coyle J. T., Schwarcz R. Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature. 1976 Sep 16;263(5574):244–246. doi: 10.1038/263244a0. [DOI] [PubMed] [Google Scholar]
  7. Cuello A. C. Central distribution of opioid peptides. Br Med Bull. 1983 Jan;39(1):11–16. doi: 10.1093/oxfordjournals.bmb.a071784. [DOI] [PubMed] [Google Scholar]
  8. Cuello A. C., Paxinos G. Evidence for a long Leu-enkephalin striopallidal pathway in rat brain. Nature. 1978 Jan 12;271(5641):178–180. doi: 10.1038/271178a0. [DOI] [PubMed] [Google Scholar]
  9. Fournie-Zaluski M. C., Chaillet P., Bouboutou R., Coulaud A., Cherot P., Waksman G., Costentin J., Roques B. P. Analgesic effects of kelatorphan, a new highly potent inhibitor of multiple enkephalin degrading enzymes. Eur J Pharmacol. 1984 Jul 20;102(3-4):525–528. doi: 10.1016/0014-2999(84)90575-2. [DOI] [PubMed] [Google Scholar]
  10. Gorenstein C., Snyder S. H. Two distinct enkephalinases: solubilization, partial purification and separation from angiotensin converting enzyme. Life Sci. 1979 Dec 10;25(24-25):2065–2070. doi: 10.1016/0024-3205(79)90198-x. [DOI] [PubMed] [Google Scholar]
  11. Hambrook J. M., Morgan B. A., Rance M. J., Smith C. F. Mode of deactivation of the enkephalins by rat and human plasma and rat brain homogenates. Nature. 1976 Aug 26;262(5571):782–783. doi: 10.1038/262782a0. [DOI] [PubMed] [Google Scholar]
  12. Horsthemke B., Hamprecht B., Bauer K. Heterogeneous distribution of enkephalin-degrading peptidases between neuronal and glial cells. Biochem Biophys Res Commun. 1983 Sep 15;115(2):423–429. doi: 10.1016/s0006-291x(83)80161-2. [DOI] [PubMed] [Google Scholar]
  13. Hughes J. Biogenesis, release and inactivation of enkephalins and dynorphins. Br Med Bull. 1983 Jan;39(1):17–24. doi: 10.1093/oxfordjournals.bmb.a071785. [DOI] [PubMed] [Google Scholar]
  14. Jessell T. M., Emson P. C., Paxinos G., Cuello A. C. Topographic projections of substance P and GABA pathways in the striato- and pallido-nigral system: a biochemical and immunohistochemical study. Brain Res. 1978 Sep 8;152(3):487–498. doi: 10.1016/0006-8993(78)91104-6. [DOI] [PubMed] [Google Scholar]
  15. Kerr M. A., Kenny A. J. The purification and specificity of a neutral endopeptidase from rabbit kidney brush border. Biochem J. 1974 Mar;137(3):477–488. doi: 10.1042/bj1370477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Koshiya K., Kato T., Tanaka R., Kato T. Brain peptidases: their possible neuronal and glial localization. Brain Res. 1984 Dec 24;324(2):261–270. doi: 10.1016/0006-8993(84)90036-2. [DOI] [PubMed] [Google Scholar]
  17. Lentzen H., Palenker J. Localization of the thiorphan-sensitive endopeptidase, termed enkephalinase A, on glial cells. FEBS Lett. 1983 Mar 7;153(1):93–97. doi: 10.1016/0014-5793(83)80125-2. [DOI] [PubMed] [Google Scholar]
  18. Malfroy B., Swerts J. P., Guyon A., Roques B. P., Schwartz J. C. High-affinity enkephalin-degrading peptidase in brain is increased after morphine. Nature. 1978 Nov 30;276(5687):523–526. doi: 10.1038/276523a0. [DOI] [PubMed] [Google Scholar]
  19. Malfroy B., Swerts J. P., Llorens C., Schwartz J. C. Regional distribution of a high-affinity enkephalin-degrading peptidase ('enkephalinase') and effects of lesions suggest localization in the vicinity of opiate receptors in brain. Neurosci Lett. 1979 Mar;11(3):329–334. doi: 10.1016/0304-3940(79)90017-x. [DOI] [PubMed] [Google Scholar]
  20. Marks N., Grynabaum A., Neidle A. On the degradation of enkephalins and endorphins by rat and mouse brain extracts. Biochem Biophys Res Commun. 1977 Feb 21;74(4):1552–1559. doi: 10.1016/0006-291x(77)90619-2. [DOI] [PubMed] [Google Scholar]
  21. Matsas R., Fulcher I. S., Kenny A. J., Turner A. J. Substance P and [Leu]enkephalin are hydrolyzed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli. Proc Natl Acad Sci U S A. 1983 May;80(10):3111–3115. doi: 10.1073/pnas.80.10.3111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Palkovits M., Brownstein M. J., Zamir N. On the origin of dynorphin A and alpha-neo-endorphin in the substantia nigra. Neuropeptides. 1984 May;4(3):193–199. doi: 10.1016/0143-4179(84)90100-8. [DOI] [PubMed] [Google Scholar]
  23. Pollard H., Llorens-Cortes C., Schwartz J. C. Enkephalin receptors on dopaminergic neurones in rat striatum. Nature. 1977 Aug 25;268(5622):745–747. doi: 10.1038/268745a0. [DOI] [PubMed] [Google Scholar]
  24. Roques B. P., Fournié-Zaluski M. C., Soroca E., Lecomte J. M., Malfroy B., Llorens C., Schwartz J. C. The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice. Nature. 1980 Nov 20;288(5788):286–288. doi: 10.1038/288286a0. [DOI] [PubMed] [Google Scholar]
  25. Semerdjian-Rouquier L., Bossi L., Scatton B. Determination of 5-hydroxytryptophan, serotonin and 5-hydroxyindoleacetic acid in rat and human brain and biological fluids by reversed-phase high-performance liquid chromatography with electrochemical detection. J Chromatogr. 1981 Nov 20;218:663–670. doi: 10.1016/s0021-9673(00)82092-0. [DOI] [PubMed] [Google Scholar]
  26. Strittmatter S. M., Lo M. M., Javitch J. A., Snyder S. H. Autoradiographic visualization of angiotensin-converting enzyme in rat brain with [3H]captopril: localization to a striatonigral pathway. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1599–1603. doi: 10.1073/pnas.81.5.1599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Vincent S., Hökfelt T., Christensson I., Terenius L. Immunohistochemical evidence for a dynorphin immunoreactive striato-nigral pathway. Eur J Pharmacol. 1982 Nov 19;85(2):251–252. doi: 10.1016/0014-2999(82)90477-0. [DOI] [PubMed] [Google Scholar]
  28. Waksman G., Bouboutou R., Devin J., Besselievre R., Fournie-Zaluski M. C., Roques B. P. Binding of the bidentate inhibitor [3H]HACBO-Gly to the rat brain neutral endopeptidase "enkephalinase". Biochem Biophys Res Commun. 1985 Aug 30;131(1):262–268. doi: 10.1016/0006-291x(85)91797-8. [DOI] [PubMed] [Google Scholar]
  29. Waksman G., Bouboutou R., Devin J., Bourgoin S., Cesselin F., Hamon M., Fournie-Zaluski M. C., Roques B. In vitro and in vivo effects of kelatorphan on enkephalin metabolism in rodent brain. Eur J Pharmacol. 1985 Nov 5;117(2):233–243. doi: 10.1016/0014-2999(85)90608-9. [DOI] [PubMed] [Google Scholar]
  30. Waksman G., Hamel E., Fournié-Zaluski M. C., Roques B. P. Autoradiographic comparison of the distribution of the neutral endopeptidase "enkephalinase" and of mu and delta opioid receptors in rat brain. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1523–1527. doi: 10.1073/pnas.83.5.1523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Westlund K. N., Denney R. M., Kochersperger L. M., Rose R. M., Abell C. W. Distinct monoamine oxidase A and B populations in primate brain. Science. 1985 Oct 11;230(4722):181–183. doi: 10.1126/science.3875898. [DOI] [PubMed] [Google Scholar]
  32. Zamir N., Palkovits M., Weber E., Mezey E., Brownstein M. J. A dynorphinergic pathway of Leu-enkephalin production in rat substantia nigra. Nature. 1984 Feb 16;307(5952):643–645. doi: 10.1038/307643a0. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES