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Generalization tests with intraventricularly applied pro-enkephalin B-derived peptides in rats trained to discriminate the opioid kappa receptor agonist ethylketocyclazocine

Abstract

Rats were trained in a two-lever food-reinforced procedure to discriminate between the effects of saline and the opioid kappa receptor agonist ethylketocyclazocine. After acquisition of this discrimination, generalization tests with opioid peptides such as β-endorphin, α-neoendorphin, dynorphin A and some dynorphin-derived peptides were conducted. The rats dose-dependently generalized the effects of intracerebroventricularly injected ethylketocyclazocine but not β-endorphin, α-neoendorphin, dynorphin A1–8, dynorphin A1–13, D-Cys2-L-Cys5-dynorphin A1–13 or dynorphin A.

D-Cys2-L-Cys5-dynorphin A1–13, in contrast to dynorphin A itself, dose-dependently caused analgesia and catatonia that was reversible with naloxone. Studies into the receptor preference of this derivative, using the technique of “selective tolerance”, revealed that this dynorphin derivative is almost devoid of kappa-receptor activity.

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References

  1. Chavkin C, Goldstein A (1981) Specific receptor for the opioid peptide dynorphin: Structure-activity relationships. Proc Natl Acad Sci USA 78:6543–6547

  2. Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the κ opioid receptor. Science 215:413–415

  3. Colpaert FC (1978) Discriminative stimulus properties of narcotic analgesic drugs. Pharmacol Biochem Behav 9:863–887

  4. Corbett AD, Paterson SJ, McKnight AT, Magnan J, Kosterlitz HW (1982) Dynorphin1–8 and dynorphin1–9 are ligands for the κ-subtype of opiate receptor. Nature 299:79–81

  5. Goldstein A, Chazarossian VE (1980) Immunoreactive dynorphin in pituitary and brain. Proc Natl Acad Sci USA 77:6207–6210

  6. Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood AL (1979) Dynorphin-(1–13), an extraordinary potent opioid peptide. Proc Natl Acad Sci USA 76:6666–6670

  7. Gramsch Ch, Höllt V, Pasi A, Mehraein P, Herz A (1982) Immunoreactive dynorphin in human brain and pituitary. Brain Res 233:65–74

  8. Han JS, Xie CW (1982) Dynorphin: potent analgesic effect in spinal cord of the rat. Life Sci 31:1781–1784

  9. Herman BH, Leslie F, Goldstein A (1980) Behavioral effects and in vivo degradation of intraventricularly administered dynorphin-(1–13) and D-Ala2-dynorphin-(1–11) in rats. Life Sci 27:883–892

  10. Höllt V, Haarmann, I, Bovermann K, Jerlicz M, Herz A (1980) Dynorphin-related immunoreactive peptides in rat brain and pituitary. Neurosci Lett 18:149–153

  11. Huidobro-Toro J, Yoshimura K, Lee NM, Loh HH, Way EL (1981) Dynorphin interaction at the κ-opiate site. Eur J Pharmacol 72:265–266

  12. Laschka E, Teschemacher H, Mehraein P, Herz A (1976) Sites and actions of morphine involved in the development of physical dependence. Psychopharmacologia 46:141–147

  13. Laurent S, Schmitt S (1983) Central cardiovascular effects of κ-agonist dynorphin-(1–13) and ethylketocyclazocine in the anesthetized rat. Eur J Pharmacol 96:165–169

  14. Leslie FM, Goldstein A (1982) Degradation of dynorphin-(1–13) by membrane-bound rat brain enzymes. Neuropeptides 2:185–196

  15. McKnight AT, Corbett AD, Kosterlitz HW (1983) Increase in potencies of opioid peptides after peptidase inhibition. Eur J Pharmacol 86:393–402

  16. Morley JE, Levine A (1983) Involvement of dynorphin and the kappa opioid receptor in feeding. Peptides 4:797–800

  17. Oka T, Negishi K, Suda M, Sawa A, Fujino M, Wakimasu M (1982) Evidence that dynorphin-(1–13) acts as an agonist on opioid κ-receptors. Eur J Pharmacol 77:137–141

  18. Pfeiffer A, Pasi A, Mehraein P, Herz A (1981) A subclassification of κ-sites in human brain by use of dynorphin 1–17. Neuropeptides 2:89–97

  19. Przewłocki R, Shearman GT, Herz A (1983) Mixed opioid nonopioid effects of dynorphin and dynorphin related peptides after their intrathecal injection in rats. Neuropeptides 3:233–240

  20. Schiller PW, Eggimann B, Nguyen TM-D (1982) Comparative structure-function studies with analogs of dynorphin-(1–13) and [Leu5]enkephalin. Life Sci 31:1777–1780

  21. Schulz R, Wüster M, Krenss H, Herz A (1980) Selective development of tolerance without dependence in multiple opioid receptors of mouse vas defenrens. Nature 285:242–243

  22. Schulz R, Wüster M, Herz A (1982) Endogenous ligands for κ-opiate receptors. Peptides 3:973–976

  23. Shearman GT, Herz A (1982a) Evidence that the discriminative stimulus properties of fentanyl and ethylketocyclazocine are mediated by an interaction with different opiate receptors (1982) J Pharmacol Exp Ther 221:735–739

  24. Shearman GT, Herz A (1982b) Discriminative stimulus properties of narcotic and non-narcotic drugs in rats trained to discriminative opiate κ-receptor agonists. Psychopharmacology 78:63–66

  25. Shearman GT, Herz A (1982c) D-Ala2, D-Leu5-enkephalin generalizes to a discriminative stimulus produced by fentanyl but not ethylketocyclazocine. Pharmacol Biochem Behav 16:249–252

  26. Tulunay FC, Jen MF, Chang JK, Loh HH, Lee NM (1981) Possible regulatory role of dynorphin on morphine and β-endorphin-induced analgesia. J Pharmacol Exp Ther 219:296–298

  27. Woo SK, Tulunay FC, Loh HH, Lee NM (1983) Effect of dynorphin-(1–13) and related peptides on respiratory rate and morphine-induced respiratory rate depression. Eur J Pharmacol 96:117–122

  28. Wüster M, Schulz R, Herz A (1980) Opiate activity and receptor selectivity of dynorphin1–13 and related peptides. Neurosci Lett 20:79–83

  29. Wüster M, Rubini P, Schulz R (1981) The preference of putative pro-enkephalins for different types of opiate receptors. Life Sci 29:1219–1227

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Correspondence to Albert Herz.

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Shearman, G.T., Schulz, R., Schiller, P.W. et al. Generalization tests with intraventricularly applied pro-enkephalin B-derived peptides in rats trained to discriminate the opioid kappa receptor agonist ethylketocyclazocine. Psychopharmacology 85, 440–443 (1985). https://doi.org/10.1007/BF00429661

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Key words

  • Drug discrimination
  • Ethylketocyclazocine
  • Dynorphin
  • Dynorphin derivatives
  • Rats