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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1985 Mar;82(6):1860–1863. doi: 10.1073/pnas.82.6.1860

Mu and kappa opioids inhibit transmitter release by different mechanisms.

E Cherubini, R A North
PMCID: PMC397375  PMID: 2984670

Abstract

The actions of various opioids were examined on calcium action potentials in the cell somata of guinea pig myenteric neurones and on the release of acetylcholine at synapses onto these cells. The opioids morphine, normorphine, and [D-Ala2, MePhe4, Met5(O)]enkephalin-ol caused membrane hyperpolarizations resulting from an increase in potassium conductance; opioids that are more selective agonists for the kappa receptor subtype (dynorphin, tifluadom, U50488H) did not. Conversely, calcium action potentials were depressed or abolished by the kappa opioids but were not affected by morphine and [D-Ala2, MePhe4, Met(O)5]enkephalin-ol. Both groups of opioids caused presynaptic inhibition of acetylcholine release in the myenteric plexus, depressing the amplitude of the fast excitatory postsynaptic potential. The presynaptic inhibition caused by [D-Ala2, MePhe4, Met(O)5]enkephalin-ol, morphine, and normorphine, but not that caused by the kappa opioids, was prevented by pretreatment with the selective mu site-directed irreversible antagonist beta-funaltrexamine. Furthermore, the presynaptic inhibitory action of morphine and [D-Ala2, MePhe4, Met(O)5]enkephalin-ol, but not that of the kappa-receptor agonists, was reversibly blocked by barium. The results suggest that presynaptic inhibition caused by mu receptor activation probably results from an increase in potassium conductance, whereas kappa-receptor agonists may depress the release of acetylcholine by directly reducing calcium entry into the nerve terminals.

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Selected References

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  1. Bixby J. L., Spitzer N. C. Enkephalin reduces calcium action potentials in Rohon-Beard neurons in vivo. J Neurosci. 1983 May;3(5):1014–1018. doi: 10.1523/JNEUROSCI.03-05-01014.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chavkin C., Goldstein A. Demonstration of a specific dynorphin receptor in guinea pig ileum myenteric plexus. Nature. 1981 Jun 18;291(5816):591–593. doi: 10.1038/291591a0. [DOI] [PubMed] [Google Scholar]
  3. Chavkin C., Goldstein A. Specific receptor for the opioid peptide dynorphin: structure--activity relationships. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6543–6547. doi: 10.1073/pnas.78.10.6543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chavkin C., James I. F., Goldstein A. Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science. 1982 Jan 22;215(4531):413–415. doi: 10.1126/science.6120570. [DOI] [PubMed] [Google Scholar]
  5. Cherubini E., Morita K., North R. A. Morphine augments calcium-dependent potassium conductance in guinea-pig myenteric neurones. Br J Pharmacol. 1984 Apr;81(4):617–622. doi: 10.1111/j.1476-5381.1984.tb16126.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cherubini E., North R. A. Inhibition of calcium spikes and transmitter release by gamma-aminobutyric acid in the guinea-pig myenteric plexus. Br J Pharmacol. 1984 May;82(1):101–105. doi: 10.1111/j.1476-5381.1984.tb16446.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Corbett A. D., Paterson S. J., McKnight A. T., Magnan J., Kosterlitz H. W. Dynorphin and dynorphin are ligands for the kappa-subtype of opiate receptor. Nature. 1982 Sep 2;299(5878):79–81. doi: 10.1038/299079a0. [DOI] [PubMed] [Google Scholar]
  8. Dunlap K. Two types of gamma-aminobutyric acid receptor on embryonic sensory neurones. Br J Pharmacol. 1981 Nov;74(3):579–585. doi: 10.1111/j.1476-5381.1981.tb10467.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gintzler A. R., Scalisi J. A. Physiological correlates of multiple subtypes of enteric opiate receptor; functional analysis of myenteric delta receptors. Brain Res. 1982 Apr 22;238(1):254–259. doi: 10.1016/0006-8993(82)90793-4. [DOI] [PubMed] [Google Scholar]
  10. Goldstein A., James I. F. Site-directed alkylation of multiple opioid receptors. II. Pharmacological selectivity. Mol Pharmacol. 1984 May;25(3):343–348. [PubMed] [Google Scholar]
  11. Hirst G. D., Spence I. Calcium action potentials in mammalian peripheral neurones. Nat New Biol. 1973 May 9;243(123):54–56. [PubMed] [Google Scholar]
  12. James I. F., Goldstein A. Site-directed alkylation of multiple opioid receptors. I. Binding selectivity. Mol Pharmacol. 1984 May;25(3):337–342. [PubMed] [Google Scholar]
  13. Kakidani H., Furutani Y., Takahashi H., Noda M., Morimoto Y., Hirose T., Asai M., Inayama S., Nakanishi S., Numa S. Cloning and sequence analysis of cDNA for porcine beta-neo-endorphin/dynorphin precursor. Nature. 1982 Jul 15;298(5871):245–249. doi: 10.1038/298245a0. [DOI] [PubMed] [Google Scholar]
  14. Kandel E. R. Calcium and the control of synaptic strength by learning. Nature. 1981 Oct 29;293(5835):697–700. doi: 10.1038/293697a0. [DOI] [PubMed] [Google Scholar]
  15. Klein M., Kandel E. R. Mechanism of calcium current modulation underlying presynaptic facilitation and behavioral sensitization in Aplysia. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6912–6916. doi: 10.1073/pnas.77.11.6912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Leslie F. M., Chavkin C., Cox B. M. Opioid binding properties of brain and peripheral tissues: evidence for heterogeneity in opioid ligand binding sites. J Pharmacol Exp Ther. 1980 Aug;214(2):395–402. [PubMed] [Google Scholar]
  17. Lord J. A., Waterfield A. A., Hughes J., Kosterlitz H. W. Endogenous opioid peptides: multiple agonists and receptors. Nature. 1977 Jun 9;267(5611):495–499. doi: 10.1038/267495a0. [DOI] [PubMed] [Google Scholar]
  18. Morita K., North R. A. Opiate activation of potassium conductance in myenteric neurons: inhibition by calcium ion. Brain Res. 1982 Jun 17;242(1):145–150. doi: 10.1016/0006-8993(82)90504-2. [DOI] [PubMed] [Google Scholar]
  19. Mudge A. W., Leeman S. E., Fischbach G. D. Enkephalin inhibits release of substance P from sensory neurons in culture and decreases action potential duration. Proc Natl Acad Sci U S A. 1979 Jan;76(1):526–530. doi: 10.1073/pnas.76.1.526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nakanishi S., Inoue A., Kita T., Nakamura M., Chang A. C., Cohen S. N., Numa S. Nucleotide sequence of cloned cDNA for bovine corticotropin-beta-lipotropin precursor. Nature. 1979 Mar 29;278(5703):423–427. doi: 10.1038/278423a0. [DOI] [PubMed] [Google Scholar]
  21. Nishi S., North R. A. Intracellular recording from the myenteric plexus of the guinea-pig ileum. J Physiol. 1973 Jun;231(3):471–491. doi: 10.1113/jphysiol.1973.sp010244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Noda M., Furutani Y., Takahashi H., Toyosato M., Hirose T., Inayama S., Nakanishi S., Numa S. Cloning and sequence analysis of cDNA for bovine adrenal preproenkephalin. Nature. 1982 Jan 21;295(5846):202–206. doi: 10.1038/295202a0. [DOI] [PubMed] [Google Scholar]
  23. North R. A. The calcium-dependent slow after-hyperpolarization in myenteric plexus neurones with tetrodotoxin-resistant action potentials. Br J Pharmacol. 1973 Dec;49(4):709–711. doi: 10.1111/j.1476-5381.1973.tb08550.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. North R. A., Tokimasa T. Muscarinic synaptic potentials in guinea-pig myenteric plexus neurones. J Physiol. 1982 Dec;333:151–156. doi: 10.1113/jphysiol.1982.sp014445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. North R. A., Williams J. T. Opiate activation of potassium conductance inhibits calcium action potentials in rat locus coeruleus neurones. Br J Pharmacol. 1983 Oct;80(2):225–228. doi: 10.1111/j.1476-5381.1983.tb10023.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pepper C. M., Henderson G. Opiates and opioid peptides hyperpolarize locus coeruleus neurons in vitro. Science. 1980 Jul 18;209(4454):394–395. doi: 10.1126/science.7384811. [DOI] [PubMed] [Google Scholar]
  27. Portoghese P. S., Larson D. L., Sayre L. M., Fries D. S., Takemori A. E. A novel opioid receptor site directed alkylating agent with irreversible narcotic antagonistic and reversible agonistic activities. J Med Chem. 1980 Mar;23(3):233–234. doi: 10.1021/jm00177a002. [DOI] [PubMed] [Google Scholar]
  28. Schultzberg M., Hökfelt T., Nilsson G., Terenius L., Rehfeld J. F., Brown M., Elde R., Goldstein M., Said S. Distribution of peptide- and catecholamine-containing neurons in the gastro-intestinal tract of rat and guinea-pig: immunohistochemical studies with antisera to substance P, vasoactive intestinal polypeptide, enkephalins, somatostatin, gastrin/cholecystokinin, neurotensin and dopamine beta-hydroxylase. Neuroscience. 1980;5(4):689–744. doi: 10.1016/0306-4522(80)90166-9. [DOI] [PubMed] [Google Scholar]
  29. Tachibana S., Araki K., Ohya S., Yoshida S. Isolation and structure of dynorphin, an opioid peptide, from porcine duodenum. Nature. 1982 Jan 28;295(5847):339–340. doi: 10.1038/295339a0. [DOI] [PubMed] [Google Scholar]
  30. Vincent S. R., Dalsgaard C. J., Schultzberg M., Hökfelt T., Christensson I., Terenius L. Dynorphin-immunoreactive neurons in the autonomic nervous system. Neuroscience. 1984 Apr;11(4):973–987. doi: 10.1016/0306-4522(84)90208-2. [DOI] [PubMed] [Google Scholar]
  31. Ward S. J., Portoghese P. S., Takemori A. E. Improved assays for the assessment of kappa- and delta-properties of opioid ligands. Eur J Pharmacol. 1982 Nov 19;85(2):163–170. doi: 10.1016/0014-2999(82)90461-7. [DOI] [PubMed] [Google Scholar]
  32. Ward S. J., Portoghese P. S., Takemori A. E. Pharmacological characterization in vivo of the novel opiate, beta-funaltrexamine. J Pharmacol Exp Ther. 1982 Mar;220(3):494–498. [PubMed] [Google Scholar]
  33. Ward S. J., Portoghese P. S., Takemori A. E. Pharmacological profiles of beta-funaltrexamine (beta-FNA) and beta-chlornaltrexamine (beta-CNA) on the mouse vas deferens preparation. Eur J Pharmacol. 1982 Jun 4;80(4):377–384. doi: 10.1016/0014-2999(82)90083-8. [DOI] [PubMed] [Google Scholar]
  34. Watson S. J., Akil H., Ghazarossian V. E., Goldstein A. Dynorphin immunocytochemical localization in brain and peripheral nervous system: preliminary studies. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1260–1263. doi: 10.1073/pnas.78.2.1260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Werz M. A., Macdonald R. L. Opioid peptides decrease calcium-dependent action potential duration of mouse dorsal root ganglion neurons in cell culture. Brain Res. 1982 May 6;239(1):315–321. doi: 10.1016/0006-8993(82)90859-9. [DOI] [PubMed] [Google Scholar]
  36. Williams J. T., Egan T. M., North R. A. Enkephalin opens potassium channels on mammalian central neurones. Nature. 1982 Sep 2;299(5878):74–77. doi: 10.1038/299074a0. [DOI] [PubMed] [Google Scholar]
  37. Williams J. T., North R. A. Opiate-receptor interactions on single locus coeruleus neurones. Mol Pharmacol. 1984 Nov;26(3):489–497. [PubMed] [Google Scholar]
  38. Yoshimura M., North R. A. Substantia gelatinosa neurones hyperpolarized in vitro by enkephalin. Nature. 1983 Oct 6;305(5934):529–530. doi: 10.1038/305529a0. [DOI] [PubMed] [Google Scholar]

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