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d-ala2-methionine-enkephalinamide self-administration in the morphine-dependent rat

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Abstract

The self-administration of d-enkephalin was studied in the dependent rat self-administering morphine. The rats were prepared with chronic IV and bilateral intraventricular (IVT) injection cannulae. They were made physically dependent on morphine and trained to lever press for IV morphine self-injections (inj) (10 mg/kg) on a fixed ratio (20) (FR20) schedule of reinforcement. Substitution of d-enkephalin either IVT. (40 μg/inj) or IV (10 mg/kg/inj) in the morphinedependent rat maintained consistent lever pressing and self-administration.behavior similar to morphine self-administration. No signs of abstinence were observed during the d-enkephalin substitution. However, saline substitution (0,05 ml/inj IV) for morphine in the self-administering rat produced an abstinence syndrome characterized by extinction of responding, wet-dog shakes, writhes, and diarrhea, which were reversed for 1 h by a single IVT injection of d-enkephalin (40 or 80 μg). These results indicate that d-enkephalin will serve as a reinforcer to maintain opiate-seeking behavior and support physical dependence in the rat.

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References

  1. Barchas, J. D., Akil, H., Elliot, G. R., Holman, R. B., Watson, S. J.: Behavioral neurochemistry: Neuroregulators and behavioral states. Science 200, 964–973 (1978)

  2. Belluzzi, J. D., Stein, L.: Enkephalin may mediate cuphoria and drive-reduction reward. Nature 226, 556–558 (1977)

  3. Bhargava, N. N.: New in vivo evidence for narcotic agonistic property of leucine-enkephalin. J. Pharm. Sci 67, 136–137 (1978)

  4. Bläsig, J., Herz, A.: Tolerance and dependence induced by morphinelike pituitary peptides in rats. Naunyn Schmiedebergs Arch. Pharmacol 294, 297–300 (1976)

  5. Deneau, G. A., Yanagita, T. M., Seevers, M. M.: Self-administration of psychoactive substances by the monkey. Psychopharmacologia 16, 30–48 (1969)

  6. Gianutsos, G., Drawbaugh, R., Hynes, M., Lal, H.: The narcotic withdrawal syndrome in the rat. In: Methods in narcotic research. S. Ehrenpreis, A. Neidle, eds., pp. 293–309, New York: Marcel Dekker 1975

  7. Henriksen, S. J., Bloom, F. E., McCoy, F., Ling, N., Guillemin, R.: β-Endorphin induces nonconvulsive limbic seizures. Proc. Natl. Acad. Sci. USA 75, 5221–5225 (1978)

  8. Hughes, J., Smith, T. W., Kosterlitz, H. W., Rothergill, L. A., Morgan, B. A., Morris, H. R.: Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258, 577–579 (1975)

  9. Khazan, N.: Implication and significance of EEG and sleep-awake activity in the study of experimental drug dependence on morphine. In: Methods in narcotic research, S. Ehrenpreis, A. Neidle, eds., pp. 173–215. New York: Marcel Dekker 1975

  10. Kosterlitz, H. W., Hughes, J.: Some thoughts on the significance of enkephalin, the endogenous ligand. Life Sci. 17, 91–96 (1975)

  11. Mello, N. K., Mendelson, J. H.: Self-administration of an enkephalin analog by rhesus monkey. Pharmacol. Biochem. Behav. 9, 579–586 (1978)

  12. Moreton, J. E., Meisch, R. A., Stark, L. M., Thompson, T.: Ketamine self-administration by the rhesus monkey. J. Pharmacol. Exp. Ther. 203, 303–309 (1977)

  13. Moreton, J. E., Roehrs, T., Khazan, N.: Drug self-administration and sleep-awake activity in rats dependent on morphine, methadone, or l-alpha-acetylmethadol. Psychopharmacology 47, 237–241 (1976)

  14. Noble, E. P., Wurtman, R. J., Axelrod, J.: A simple and rapid method for injecting 3H-norepinephrine into the lateral ventricle of the rat brain. Life Sci. 6, 218–291 (1967)

  15. North, R. A., Karras, P. J.: Opiate tolerance and dependence induced in vitro in single myenteric neurons. Nature 272, 73–75 (1978)

  16. Pasternak, G. W., Goodman, R., Snyder, S. H.: An endogenous morphine-like factor in mammalian brain. Life Sci. 16, 1765–1769 (1975)

  17. Schulz, R., Herz, A.: Dependence liability of enkephalin in the myenteric plxus of the guinea pig. Eur. J. Pharmacol. 39, 429–432 (1976)

  18. Teschemacher, H., Opheim, K. E., Cox, B. M., Goldstein, A.: A peptide-like substance from pituitary that acts like morphine. Isolation. Life Sci. 16, 1771–1776 (1975)

  19. Thompson, T., Schuster, C. R.: Morphine self-administration, food reinforced and avoidance behaviors in rhesus monkeys. Psychopharmacologia 5, 87–94 (1964)

  20. Tortella, F. C., Moreton, J. E., Khazan, N.: Electroencephalographic and behavioral effects of d-ala2-methionine-enkephalinamide and morphine in the rat. J. Pharmacol. Exp. Ther. 206, 636–643 (1978)

  21. Tortella, F. C., Moreton, J. E., Khazan, N.: Electroencephalographic and behavioral tolerance to and cross-tolerance between d-ala2-methionine-enkephalinamide and morphine in the rat. J. Pharmacol. Exp. Ther. 201, 174–179 (1979)

  22. Tseng, L. F., Loh, H. H., Li, C. H.: β-Endorphin: Cross-tolerance to and cross-physical dependence on morphine. Proc. Natl. Acad. Sci. USA 73, 4187–4189 (1976)

  23. Urea, G.,Frenk, H., Liebeskind, J. C., Taylor, A. N.: Morphine and enkephalin: Analgesic and epileptic properties. Science 197, 83–86 (1977)

  24. Ree, J. M. van, Smyth, D. G., Colpaert, F. C.: Dependence-creating properties of lipotropin C-fragment (β-endorphin): Evidence for its internal control of behavior. Life Sci. 24, 495–502 (1979)

  25. Waterfield, A. A., Hughes, J., Kosterlitz, H. W.: Cross-tolerance between morphine and methionine-enkephalin. Nature 260, 624–625 (1976)

  26. Weeks, J. R.: Experimental morphine addiction: Method for automatic intravenous injections in unrestrained rats. Science 138, 143–144 (1962)

  27. Weeks, J. R.: Long-term intravenous infusion. In: Methods in psychobiology, vol. 2, R. D. Myers, ed., pp. 155–168 London, New York. Academic 1972

  28. Weeks, J. R., Collins, R. J.: Factors affecting voluntary morphine intake in self-maintained addicted rats. Psychopharmacologia 6, 267–279 (1964)

  29. Weeks, J. R., Collins, R. J.: Dose and physical dependence as factors in the self-administration of morphine by rats. Psychopharmacology 65, 171–177 (1979)

  30. Wei, E. T., Loh, H. H.: Physical dependence on opiate-like peptides. Science 193, 1262–1263 (1976)

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Correspondence to J. Edward Moreton.

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Tortella, F.C., Edward Moreton, J. d-ala2-methionine-enkephalinamide self-administration in the morphine-dependent rat. Psychopharmacology 69, 143–147 (1980). https://doi.org/10.1007/BF00427640

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Key words

  • Enkephalin
  • Morphine
  • Self-administration
  • Narcotic
  • Drug-reinforcement behavior