Molecular Pharmacology, Vol 18, 395-401, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Lack of Cross-Tolerance on Multiple Opiate Receptors in the Mouse Vas Deferens

¹ Department of Neuropharmacology, Max-Planck-Institut für Psychiatrie, Kraepelinstrasse 2, D-8000 München 40, Federal Republic of Germany

The development of opiate tolerance has been studied in the mouse vas deferens, which contains µ- and -opiate receptors. Long-term infusion of opioids acting selectively on either µ- or -receptors was accomplished by means of osmotic minipumps. In vitro tests of vasa deferentia from chronically [D-Ala²,D-Leu⁵]enkephalin (DADL)-treated mice revealed an 800-fold degree of tolerance for -receptors, while µ-receptors were left unaffected. Accordingly, cross-tolerance to -receptor agonists, e.g., leucine-enkephalin, was observed but not to µ-receptor agonists, e.g., normorphine. On the other hand, infusion of the potent opioid sufentanyl, which almost selectively acts at µ-receptors, brings about a high degree of tolerance for µ-receptor agonists, but causes no change in sensitivity to -receptor agonists. A number of opioids, including -endorphin, exhibit some degree of cross-tolerance in -receptor-tolerant as well as in µ-receptor-tolerant preparations. Essentially identical results were obtained in vasa deferentia made acutely tolerant in vitro using the -receptor agonist DADL. Challenge of highly tolerant vasa deferentia with the narcotic antagonist naloxone failed to demonstrate any withdrawal sign. The failure to demonstrate dependence in highly tolerant vasa deferentia may be due to adaptational processes upon chronic opioid exposure at the opiate receptor binding site level. It is concluded that opiate receptor differentiation can be reliably achieved by means of their selective tolerance development.

Note:
ACKNOWLEDGMENTS The expert technical assistance of Ms. A. Wilhelm is greatly appreciated. We would like to thank Dr. J. Dum for stylistic corrections of the manuscript. We are grateful to Dr. Heykants for donating sufentanyl and to Dr. Ling for a gift of -lipotropin_61-79.

This article has been cited by other articles:

				K. Rice, A. Jacobson, T. Burke Jr, B. Bajwa, R. Streaty, and W. Klee Irreversible ligands with high selectivity toward delta and mu opiate receptors Science, April 15, 1983; 220(4594): 314 - 316. [Abstract] [PDF]