Receptor endocytosis counteracts
the development of opioid tolerance

Koch T, Widera A, Bartzsch K, Schulz S,
Brandenburg LO, Wundrack N,
Beyer A, Grecksch G, Hollt V.
Otto-von-Guericke University.
Mol Pharmacol. 2004 Oct 8


In contrast to endogenous opioids, the highly addictive drug morphine activates the micro-opioid receptor without causing its rapid endocytosis. Recently, it has been reported, that coapplication of low concentrations of [D-Ala(2)-MePhe(4)-Gly(5)-ol] enkephalin (DAMGO) facilitates the ability of morphine to stimulate micro-opioid receptor endocytosis and prevents the development of morphine tolerance in rats. To investigate the clinical relevance of this finding for analgesic therapy the endocytotic efficacies of a series of clinically used opioids were determined and the effect of a combination of these drugs with morphine on the micro-opioid receptor endocytosis in receptor expressing HEK293 cells quantified. Combination of morphine and opioid drugs with high endocytotic efficacies (e.g. DAMGO, etonitazene, sufentanil, beta-endorphin, piritramide, or methadone) did not result in a facilitation of morphine-mediated endocytosis but rather in a decrease of the receptor endocytosis mediated by the tested opioid drugs. These findings demonstrate a partial agonistic effect of morphine on the agonist-induced receptor endocytosis. Moreover, we demonstrated that the endocytotic potencies of opioid drugs are negatively correlated with their ability to cause receptor desensitization and opioid tolerance in HEK293 cells. These results strongly support the hypothesis that micro-opioid receptor endocytosis counteracts receptor desensitization and opioid tolerance by inducing fast receptor reactivation and recycling. In addition it is shown that agonist-induced receptor endocytosis facilitates the compensatory upregulation of the cAMP pathway, a cellular hallmark of opioid withdrawal. Our findings suggest that opioids with high endocytotic efficacies might cause reduced opioid tolerance but can facilitate compensatory mechanisms resulting in an enhanced opioid dependence.
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