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Morphine- and methadone-tolerant mice differ in cross-tolerance to other opiates

Heterogeneity in opioid mechanisms indicated

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Summary

Mice were rendered tolerant to morphine or l-methadone by subcutaneous injections for 4 days. The antinociceptive activities of morphine, codeine, l-methadone and d-propoxyphene were determined in tolerant and control mice using the hot-plate test, and the respective ED50's were calculated by the up-and-down procedure of Dixon. An asymmetry in cross-tolerance patterns was found: While morphine-pretreated mice were tolerant to morphine only (with a dose-ratio tolerant: control of 5.2), methadonepretreated mice were tolerant to all analgesics tested, and more so to morphine than to methadone itself (dose-ratios: morphine 5.2; l-methadone 3.0; codeine 2.7 and d-propoxyphene 1.9).

The results are discussed in terms of heterogeneity in opioid receptor mechanisms.

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References

  • Adler TK (1963) The comparative potencies of codeine and its demethylated metabolites after intraventricular injection in the mouse. J Pharmacol Exp Ther 140:155–161

    Google Scholar 

  • Basbaum AI, Fields HL (1978) Endogenous pain control mechanisms: Review and hypothesis. Ann Neurol 4:451–462

    Google Scholar 

  • Brown JH, Garrett RL (1972) Relative degree of tolerance to morphine sulfate and methadone hydrochloride in the rat and the interaction of dexamethasone. Arch Int Pharmacodyn 196:176–183

    Google Scholar 

  • Cochin J, Axelrod J (1959) Biochemical and pharmacological changes in the rat following chronic administration of morphine, nalorphine and normorphine. J Pharmacol Exp Ther 125:105–110

    Google Scholar 

  • Dixon WJ (1965) The up-and-down method for small samples. J Am Statist Assoc 60:967–978

    Google Scholar 

  • Dixon WJ (1980) Efficient analysis of experimental observations. Ann Rev Pharmacol Toxicol 20:441–462

    Google Scholar 

  • Dole VP, Nyswander ME, Kreek MJ (1966) Narcotic blockade. Arch Intern Med 118:304–309

    Google Scholar 

  • Egan TM, North RA (1981) Both μ and δ opiate receptors exist on the same neuron. Science 214:923–924

    Google Scholar 

  • Goodman RR, Snyder SH, Kuhar MJ, Young WS (1980) Differentiation of delta and mu opiate receptor localization by light microscopic autoradiography. Proc Natl Acad Sci 77:6239–6243

    Google Scholar 

  • Jaffe JH, Martin WR (1980) Opioid analgesics and antagonists. In: Gilman AG, Goodman LS, Gilman A (eds), The pharmacological basis of therapeutics, 6th ed. MacMillan, New York, pp 494–534

    Google Scholar 

  • Martin WR (1981) Multiple opioid receptors. Life Sci 28:1457–1554

    Google Scholar 

  • Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532

    Google Scholar 

  • Masten LW, Peterson GR, Burkhalter A, Way EL (1975) Microsomal enzyme induction by methadone and its implications on tolerance to methadone lethality. Nature (Lond.) 253:200–202

    Google Scholar 

  • Masten LW, Peterson GR, Burkhalter A, Way EL (1980) Tolerance to methadone lethality and microsomal enzyme induction in mice tolerant to and dependent on morphine. Drug Alc Depend (Lausanne) 5:27–37

    Google Scholar 

  • McMillan DE, McGivney WT, Harwick WC (1981) Effects of drugs on behaviour in rats maintained on morphine, methadone or pentobarbital. J Pharmacol Exp Ther 215:9–14

    Google Scholar 

  • Neil A, Terenius L (1981) d-Propoxyphene acts differently from morphine on opioid receptor-effector mechanisms. Eur J Pharmacol 69:33–39

    Google Scholar 

  • Orahovats PD, Lehman EG (1958) Studies with normorphine in animals. J Pharmacol Exp Ther 122:58A

    Google Scholar 

  • Schulz R, Wüster M (1981) Are there subtypes (isoreceptors) of multiple opiate receptors in the mouse vas deferens? Eur J Pharmacol 76:61–66

    Google Scholar 

  • Schulz R, Wüster M, Kreuss H, Herz A (1980) Lack of cross-tolerance on multiple opiate receptors in the mouse vas deferens. Mol Pharmacol 18:395–401

    Google Scholar 

  • Su T-P, Clements TH, Gorodetzky CW (1981) Multiple opiate receptors in guinea-pig ileum. Life Sci 28:2519–2528

    Google Scholar 

  • Tennant FS, Russell BA, Casas SK, Bleich RN (1975) Heroin detoxification. A comparison of propoxyphene and methadone. J Am Med Ass 232:1019–1022

    Google Scholar 

  • Way EL, Adler TK (1960) The pharmacologic implications of the fate of morphine and its surrogates. Pharmacol Rev 12:383–446

    Google Scholar 

  • Williams JT, Zieglgänsberger W (1981) Neurons in the frontal cortex of the rat carry multiple opiate receptors. Brain Res 226:304–308

    Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Pharmacology, Uppsala University, Box 573, S-751 23, Uppsala, Sweden

    Anders Neil

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Neil, A. Morphine- and methadone-tolerant mice differ in cross-tolerance to other opiates. Naunyn-Schmiedeberg's Arch. Pharmacol. 320, 50–53 (1982). https://doi.org/10.1007/BF00499071

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  • DOI: https://doi.org/10.1007/BF00499071

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