Effects of Opiate Drugs on the Metabolism of Calcium in Synaptic Tissue

  • David H. Ross


Pharmacological actions of opiate drugs are characterized by analgesia, respiratory depression and sedation or CNS depression. These parameters together with changes in body temperature may be observed after a single dose of the opiate agonist. However, repeated administration of the drug at a constant dose or the necessity to increase the dose to achieve the same degree of response produces an effect commonly referred to as tolerance. This effect, although easily produced by opiate drugs, is clearly one of the least understood events in all of narcotic research.


Tyrosine Hydroxylase Adenylate Cyclase Opiate Receptor Synaptic Membrane Cyclic Nucleotide Phosphodiesterase 
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. Abood, L. G., 1969, Calcium-adenosine tri-phosphate-lipid interactions and their significance in the excitatory membrane, Neurosoi. Res. 2: 42.Google Scholar
  2. Axelrod, J., 1956, The enzymatic N-demethylation of narcotic drugs, J. Pharmacol. Exp. Ther. 117: 322.Google Scholar
  3. Blaustein, M. P., 1975, Effects of potassium, veratridine, and scorpion venom on Ca accumulation and transmitter release by nerve terminal in vitro3 J. Physiol. ( London ) 247: 617.Google Scholar
  4. Blaustein, M. P., 1967, Phospholipids as ion exchanges: Implications for a possible role in biological membranes excitability and anesthesia, Bioohim. Biophys. Acta 135: 653.Google Scholar
  5. Blaustein, M. P., and Goldman, D. E., 1966, Competitive action of calcium and procaine on lobster axon, J. gen. Physiol. 49: 1043.Google Scholar
  6. Blaustein, M. P., Johnson, E. M., and Needleman, P., 1972, Calcium dependent norepinephrine release from presynaptic nerve endings in vitro, Proo. Nat. Aoad. Soi. U. S. A: 69: 2237.Google Scholar
  7. Bonnet, K. A., and Gusik, S., 1977, Enkephalin and moihirie: Brain adenylate cyclase effects and calciumion, Trans. Amer. Soo. Neuroohem. 8: 84.Google Scholar
  8. Brostrom, C. 0., Huang, Y. C., Breckenridge, B. McL., and Wolff, D. J., 1975, Identification of a calcium binding protein_as a calcium dependent regulator of brain adeny 1 ate cy_c 1 ase, Proo. Nat. Aoad. Soi. U. S. A. 72: 64.Google Scholar
  9. Brooks, J. C., and Siegel, F. L., 1973, Identification of a calcium binding phosphoprotein from beef adrenal medulla, J. Biol. Chem. 248: 4189.Google Scholar
  10. Cardenas, H. L., and Ross, D. H., 1976, Calcium depletion of synaptosomes after morphine treatment, Brit. J. Pharmacol. 57: 521.Google Scholar
  11. Cardenas, H. L., and Ross, D. H., 1975, Morphine-induced depletion of calcium in discrete regions of rat brain, J. Neuroohem. 24: 487.Google Scholar
  12. Childers, S. R., and Siegel, F. L., 1975, Isolation and purification of a calcium binding protein from electroplax of electro- phorus electricus, Bioohim. Biophys. Aota 405: 99.Google Scholar
  13. Cho, T. M., Cho, J. S., and Loh, H. H., 1976, 3H-cerebroside sulfate redistribution induced by cation opiate or phosphatidyl serine, Life Soi. 19: 117.Google Scholar
  14. Clouet, D. H., and Iwatsubo, E., 1975, Mechanisms of tolerance to and dependence on narcotic analgesic drugs, Annu. Rev. Pharmacol. 15: 49.Google Scholar
  15. Cochin, J., and Axelrod, J., 1959, Biochemical and pharmacological changes in the rat following chronic administration of morphine, nalorphine and normorphine, J. Pharmacol. Exp. Ther. 125: 105.Google Scholar
  16. Collier, H. 0. J., 1966, Tolerance, physical dependence and receptors, Adv. in Drug Res. 3: 171.Google Scholar
  17. Cox, B. M., and Osman, 0., 1970, Inhibition of the development of tolerance to morphine in rats by drugs which inhibit ribonucleic acid or protein synthesis, Brit. J. Pharmacol. 38: 157.Google Scholar
  18. Dole, V. P., 1970, The biochemistry of addiction, Annu. Rev. Biochem. 39: 821.Google Scholar
  19. Douglas, W. W., 1968, Stimulus-secretion coupling, the concept and clues from chromaffin and other cells, Brit. J. Pharmacol. 34: 451.Google Scholar
  20. Ferrendelli, J. A., Kinscherf, D. A., and Chang, M. M., 1973, Regulation of levels of guanosine cyclic 31 5′ monophosphate in the central nervous system: Effects of depolarizing agents, Mol. Pharmacol. 9: 445.Google Scholar
  21. Frank, G. B., 1968, Drugs which modify membrane excitability, Fed. Proc. 27: 132.Google Scholar
  22. Goldstein, A., and Goldstein, D. B., 1968, Enzyme expansion theory of drug tolerance and physical dependence, in “The Addictive States” (A. Wikler) pp. 265–267, Williams and Wilkins, Baltimore.Google Scholar
  23. Hano, K., 1968, Calcium content in mouse brain after exposure to morphine, Jpn. J. Pharmacol. 17: 135.Google Scholar
  24. Harris, R. A., Loh, H. H., and Way, E. L., 1976, Antinociceptive effects of lanthanum and cerium in non-tolerant and morphine tolerant-dependent animals, J. Pharmacol. Exp. Ther. 196: 288.Google Scholar
  25. Harris, R. A., Loh, H. H., and Way, E. L., 1975, Effects of divalent cation, cation chelators and an ionophore on morphine analgesia and tolerance, J. Pharmacol. Exp. Ther. 195: 488.Google Scholar
  26. Harris, R. A., Yamamoto, H., Loh, H. H., and Way, E. L., 1976, Alterations in brain calcium localization during the development of morphine tolerance and dependence, in “Opiates and Endogenous Opioid Peptides”, (H. W. Kosterlitz), pp. 361- 368, Elsevier-North Holland Biomed. Press, Amsterdam.Google Scholar
  27. Harris, R. A., Yamamoto, H., Loh, H. H., and Way, E. L., 1977, Discrete changes in brain calcium with morphine analgesia, tolerance-dependence and abstinence, Life Sci. 20: 501.PubMedCrossRefGoogle Scholar
  28. Hitzeman, R. J., Hitzeman, B. A., and Loh, H. H., 1974, Binding of 3H-naloxone in the mouse brain: Effects of ions and tolerance development, Life Sci. 14: 2393.Google Scholar
  29. Ho, I. K., and Desaiah, D., 1977, Effect of morphine on mouse brain ATPase activity, Biochem. Pharmacol. 26: 89.Google Scholar
  30. Ho III, V., Dum, J., Blasig, J., Schubert, P., and Herz, A., 1975, Comparison of in vivo and in vitro parameters of opiate receptor binding in naive and tolerant/dependent rodents, Life Sci. 16: 1823.CrossRefGoogle Scholar
  31. Hug, C. C., 1972, Characteristics and theories related to acute and chronic tolerance development, in “CRC Chemical and Biological Aspects of Drug Dependence”, (S. J. Mule and H. Brill) pp. 307 - 359, CRC Press, Cleveland.Google Scholar
  32. Iverson, L. L., and Minneman, K. P., 1977, Interaction of dopamine receptors and opiate drugs in mammalian brain, Trans. Amer. Soc. Neurochem. 8: 108.Google Scholar
  33. Kakiuchi, S., Yamazaki, R., Teshima, Y., and Uenishi, K., 1973, Regulation of nucleoside cyclic 31:5f monophosphate phosphodiesterase activity from rat brain by a modulator and Ca++, Proc. Nat. Acad. Soi. U. S. A. 70: 3526.Google Scholar
  34. Kakiuchi, S., Yamazaki, R., Teshima, Y., Uenshi, K., and Miyamoto, E., 1975, Multiple cyclic nucleotide phosphodiesterase activities from rat tissues and occurrence of a Ca++ + Mg++ ion dependent phosphodiesterase and its protein activator, Biochem. J. 146: 109.Google Scholar
  35. Kakunaga, T., Kaneto, H., and Hano, K., 1966, Pharmacologic studies on analgesia significance of the calcium ion in morphine analgesia, J. Pharmacol. Exp. Ther. 153: 134.Google Scholar
  36. Kamino, K., Uyesaka, N., Ogawa, M., and Inonye, A., 1975, Ca++ binding of synaptosomes isolated from rat brain cortex II. Inhibitory effects of magnesium and other cations, J. Memb. Biol. 21: 113.Google Scholar
  37. Katz, B., and Miledi, R., 1965, The effect of calcium on acetylcholine release from motor nerve terminals, Proa. R. Soc. Biol. London3 Ser. B 161: 496.CrossRefGoogle Scholar
  38. Klee, W. A., Sharma, S. K., and Nirenberg, M., 1975, Opiates receptors as regulators of adenylate cyclase, Life. Sci. 16: 1869.Google Scholar
  39. Klee, W. A., and Streaty, R. A., 1974, Narcotic receptor sites in morphine dependent rats, Nature 248: 61.PubMedCrossRefGoogle Scholar
  40. Knapp, S., Mandell, A. J., and Bullard, W. P., 1975, Calcium activation of brain tryptophan hydroxylase, Life Sci. 16: 1583.PubMedCrossRefGoogle Scholar
  41. Llinas, R., and Nicholson, C., 1975, Calcium role in depolarization-secretion coupling: an aequorin study in the squid giant synapse, Proc. Nat. Acad. Sci. U. S. A. 72: 187.Google Scholar
  42. Mahendran, C., Nicklas, W. J., and Berl, S., 1974, Evidence for calcium-sensitive components in brain actomyosin-like protein (neurostenin), J. Neurochem. 23: 497.PubMedCrossRefGoogle Scholar
  43. Minneman, K. P., and Iverson, L. L., 1976, Enkephalin and opiate narcotics increase cyclic GMP accumulation in slices of rat neostriatum, Nature 262: 313.PubMedCrossRefGoogle Scholar
  44. Morgenroth, V. H., Boadle-Biber, M. C., and Roth, R. H., 1975, Activation of tyrosine hydroxylase from central noradrenergic neurons by calcium, Mol. Pharmacol. 11: 427.Google Scholar
  45. Mule, S. J., 1971, Phospholipid metabolism in narcotic drugs, in “Biochemical Pharmacology” (D. H. Clouet) pp. 190 - 214, Plenum Press, New York.Google Scholar
  46. Olson, D. R., Kon, C., and Breckenridge, B. McL., 1976, Calcium ion effects on guanylate cyclase of brain, Life Sci. 18: 935.PubMedCrossRefGoogle Scholar
  47. Pasternak, G. W., Snowman, A. M., and Snyder, S. H., 1975, Selective enhancement of (3H) opiate agonist binding by divalentcations, Mol. Pharmacol. 11: 735.Google Scholar
  48. Pert, C. B., and Snyder, S. H., 1974, Opiate receptor binding of agonist and antagonists affected differentially by sodium, Mol. Pharmacol. 10: 868.Google Scholar
  49. Pert, C. B., and Snyder, S. H., 1973, Properties of opiate receptor binding in rat brain, Proc. Nat. Acad. Sci. U. S. A. 70: 2243.Google Scholar
  50. Racagni, G., Zsilla, G., Giudotli, A., and Costa, E., 1976, Accumulation of cGMP in striatum of rats injected with narcotic analgesics: Antagonism by naltrexone, J. Pharm. Pharmacol. 28: 258.Google Scholar
  51. Rao, K. N., de Smit, M., Howells, A. J., and Bygrave, F. L., 1974, Inhibition of Ca++ of t-RNA amino-acylation in preparation of rat liver, FEBS Lett. 41: 185.Google Scholar
  52. Ray, A. K., 1971, Inhibition of the alanine t-RNA amine acylation by Ca++, Biochim. Biophys. Acta 246: 349.Google Scholar
  53. Ray, A. K., Mukherji, M., and Ghosh, J. J., 1968, Adrenal catecholamines and related changes during different phases of morphine administration — A histochemical study, J. Neurochem. 15: 875.PubMedCrossRefGoogle Scholar
  54. Reis, D. J., Hess, P., and Azmitia, E. C., 1970, Changes in enzymes subserving catecholamine metabolism in morphine tolerance and withdrawal in rats, Brain Res. 20: 309.PubMedCrossRefGoogle Scholar
  55. Ross, D. H., 1977, Calcium content and binding in synaptosomal subfractions during chronic morphine treatments, Neurochemical Res. 2: 581.CrossRefGoogle Scholar
  56. Ross, D. H., 1975, Tolerance to morphine induced calcium depletion, Brit. J. Pharmacol. 55: 431.Google Scholar
  57. Ross, D. H., and Cardenas, H. L., 1977, Levorphanol inhibition of Ca++ binding to synaptic membranes in vitro3 Life Sci. 20: 1455.Google Scholar
  58. Ross, D. H., and Lynn, S. C., 1975, Characterization of acute tolerance to morphine using reserpine and cycloheximide, Biochem. Pharmacol. 24: 1135.Google Scholar
  59. Ross, D. H., Lynn, S. C., and Cardenas, H. L., 1976, Selective control of calcium levels by naloxone, Life Sci. 18: 789.PubMedCrossRefGoogle Scholar
  60. Ross, D. H., Medina, M. A., and Cardenas, H. L., 1974, Morphine and ethanol: selective depletion of regional brain calcium, Science 186: 63.PubMedCrossRefGoogle Scholar
  61. Seeman, P., 1972, The membrane actions of anesthetics and tranquilizers, Pharmacol. Rev. 24: 583.Google Scholar
  62. Sharma, S. K., Nirenberg, M., and Klee, W. A., 1975, Morphine receptors as regulators of adenylate cyclase activity, Proc. Nat. Acad. Sci. U. S. A. 72: 590.Google Scholar
  63. Shuster, L., 1961, Repression and de-repression of enzyme synthesis as a possible explanation of some aspects of drug action, Nature 189: 314.CrossRefGoogle Scholar
  64. Simon, E. J., Hiller, J. M., and Edelman, I., 1973, Stereospecific binding of the potent narcotic analgesic (3H)-etorphine to rat brain homogenate, Proc. Nat. Acad. Sci. U. S. A. 70: 1947.Google Scholar
  65. Simon, E. J., Hiller, J. M., Groth, J., and Edelman, I., 1975, Further properties of stereospecific opiate binding sites in rat brain on the nature of the sodium effect, J. Pharmacol. Exp. Ther. 192: 531.Google Scholar
  66. Somlyo, A. V., and Somlyo, A. P., 1968, Vascular smooth muscle I. normal structure pathology, biochemistry and biophysics, Pharmacol. Rev. 20: 197.Google Scholar
  67. Stahl, W. L., and Swanson, P. D., 1971, Movements of calcium and other cations in isolated cerebral tissue, J. Nevcrochem. 18: 415.CrossRefGoogle Scholar
  68. Swanson, P. D., Anderson, L., and Stahl, P. D., 1974, Uptake of calcium ions by synaptosomes from rat brain, Biochim. Biophys. Acta 356: 174.Google Scholar
  69. Tasaki, I., 1968, “Nerve excitation: A macromolecular approach”, Thomas Inc., Springfield.Google Scholar
  70. Teo, T. S., and Wang, J. H., 1973, Mechanism of activation of cyclic adenosine 3f:5f-monophosphate phosphodiesterase from bovine heart by calcium ions, J. Biol. Chem. 248: 5950.Google Scholar
  71. Teshima, Y., and Kakiuchi, S., 1974, Mechanism of stimulation of Ca+2 plus Mg+2 dependent phosphodiesterase from rat cerebral cortex by the modulator protein and Ca+2, Biochem. Biophys. Res. Comm. 56: 489.Google Scholar
  72. Weiss, G. B., 1974, Cellular pharmacology of lanthanum, Annu. Rev. Pharmacol. 14: 343.Google Scholar
  73. Wolff, D. J., Huebner, J. A., and Siegel, F. L., 1972, Calcium binding phosphoprotein of pig brain effects of cations on the calcium binding, J. Neurochem. 19: 2855.PubMedCrossRefGoogle Scholar
  74. Wolff, D. J., and Siegel, F. L., 1972, Purification of a calcium-binding phosphoprotein from pig brain, J. Biol. Chem. 247: 4180.Google Scholar
  75. Yoshida, H., and Ichida, S., 1974, Effects of Na+ on Ca++ uptake of the synaptic plasma membrane, Life Sci. 15: 685.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1978

Authors and Affiliations

  • David H. Ross
    • 1
    • 2
  1. 1.Department of PharmacologyThe University of Texas Health Science CenterSan AntonioUSA
  2. 2.Department of PsychiatryThe University of Texas Health Science CenterSan AntonioUSA

Personalised recommendations