Summary
The analgesic effect of tilidine in rats is completely antagonized by the narcotic antagonist naloxone. Radioreceptor assays revealed, however, that the main metabolites of tilidine, nortilidine and bisnortilidine, rather than tilidine exhibit affinity to opiate receptors. These findings were confirmed in studies using the electrically stimulated guinea pig ileum and the mouse vas deferens. Chronic tilidine administration to rats caused a considerable degree of physical dependence, which was expected from the ability of the intact animal to metabolize tilidine. In the isolated ileum from chronically morphinized guinea pigs, both nortilidine and bisnortilidine fully substituted for morphine in preventing induction of withdrawal, indicating dependence liability of these metabolites.
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Bläsig, J., Herz, A., Reinhold, K., Zieglgänsberger, S.: Development of physical dependence on morphine in respect to time and dosages and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia (Berl.) 33, 19–38 (1973)
Ehrenthal, W., Pfleger, K.: The use of exact mass measurement with a GC-MS-instrument in toxicological analysis. Acta pharmacol. (Kbh.) 41 (11), 199–211 (1977)
Gibson, R. D., Tingstad, J. E.: Formulation of a morphineimplantation pellet suitable for tolerance-physical dependence studies in mice. J. pharm. Sci. 59, 426–427 (1970)
Goldstein, A., Schulz, R.: Morphine-tolerant longitudinal muscle strip from guinea pig ileum. Brit. J. Pharmacol. 48, 655–666 (1973)
Herrmann, M., Steinbrecher, W., Heldt, W.: Zur Pharmakologie eines neuen stark wirksamen Analgeticums. Arzneimittel-Forsch. 20, 977–983 (1970)
Hoffmeister, F.: Tierexperimentelle Untersuchungen über den Schmerz und seine pharmakologische Beeinflussung. Aulendorf: Editio Cantor 1968
Hughes, J., Kosterlitz, H. W., Leslie, F. M.: Effect of morphine on adrenergic transmission in the mouse vas deferens. Assessment of agonistic and antagonistic potencies of narcotic analgesics. Brit. J. Pharmacol. 53, 371–381 (1975)
Jasinski, D. R., Martin, W. R., Hoeldtke, R.: Progress report from the clinical pharmacology section of the addiction research center. Reported to the “Committe on Problems of Drug Dependence”, pp. 6233–6247 (1969)
Jasinski, D. R., Nutt, J. G.: Progress report on the clinical assessment programm of the addiction research center. Reported to the “Committee on Problems of Drug Dependence”, pp. 108–118 (1973)
Jasinski, D. R., Griffith, J. D., Carter, C. B., Gorodetzky, C. W., Kullberg, M. P.: Progress report from the clinical pharmacology section of the addiction research center. Reported to the “Committee on Problems of Drug Dependence”, pp. 88–95 (1974)
Jurna, J., Ehrenthal, W., Pfleger, K.: Tolerance to morphine induced by chronic treatment with tilidine. Naunyn-Schmiedeberg's Arch. Pharmacol. 298, 193–195 (1977)
Kosterlitz, H. W., Watt, A. J.: Kinetic parameters of narcotic agonists and antagonists, with particular reference to N-allylnoroxymorphone (naloxone). Brit. J. Pharmacol. 33, 266–276 (1968)
Kosterlitz, H. W., Lydon, R. J., Watt, A. J.: The effect of adrenaline, noradrenaline and isoprenaline on inhibitory α-and β-adrenoceptors in the longitudinal muscle of the guinea-pig ileum. Brit. J. Pharmacol. 39, 398–413 (1970)
Lewis, J. W., Bentley, K. W., Cowan, A.: Narcotic analgesics and antagonists. A. Rev. Pharmac. 11, 241–270 (1971)
Navarro, G., Elliott, H. W., Nomof, M.: Tilidine as a model for evaluation of the pharmacology of a new potent analgesic. Clin. Pharmacol. Ther. 15, 215–223 (1974)
Pert, C. B., Snyder, S. H.: Opiate receptor: Demonstration in nervous tissue. Science 179, 1011–1014 (1973)
Pert, C. B., Snyder, S. H.: Opiate receptor binding of agonists and antagonists affected differentially by sodium. Molec. Pharmacol. 10, 868–879 (1974)
Schulz, R., Goldstein, A.: Inactivity of narcotic glucuronides as analgesics and on guinea-pig ileum. J. Pharmacol. exp. Ther. 183, 404–410 (1972)
Schulz, R., Herz, A.: The guinea-pig ileum as an in vitro model to analyse dependence liability of narcotic drugs. In: Opiates and endogenous opioid peptides (H. W. Kosterlitz, ed.), pp. 319–326. Amsterdam: Elsevier/North-Holland Biomedical Press (1976a)
Schulz, R., Herz, A.: Aspects of opiate dependence in the myenteric plexus of the guinea-pig. Life Sci. 19, 1117–1128 (1976b)
Villarreal, J. E., Seevers, M. H.: Evaluation of new compounds for morphine-like physical dependence in the Rhesus monkey. Reported to the “Committee on Problems of Drug Dependence”, pp. 10–15 (1970)
Vollmer, K.-O., Achenbach, H.: Zum Metabolismus von Dl-trans-2-Dimethylamino-1-phencyclohex-3-en-trans-1-carbonsäureäthylester-hydrochlorid. Drug Res. 24, 1237–1242 (1974)
Vollmer, K.-O., Poisson, A.: Zum Metabolismus von Dl-trans-2-Dimethylamino-1-phenyl-cyclohex-3-en-trans-1-carbon-säureäthylester-hydrochlorid (Tilidin-HCl). Drug Res. 26, 1827–1836 (1976)
Whittaker, V. P., Barker, L. A.: The subcellular fractionation of brain tissue with special reference to the preparation of synaptosomes and their component organelles. In: Methods in neurochemistry (R. Fried, ed.), Vol. 2, pp. 1–52. New York: Marcel Dekker, Inc. 1972
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Schulz, R., Bläsig, J., Wüster, M. et al. The opiate-like action of tilidine is mediated by metabolites. Naunyn-Schmiedeberg's Arch. Pharmacol. 304, 89–93 (1978). https://doi.org/10.1007/BF00495543
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DOI: https://doi.org/10.1007/BF00495543