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• W2022337168 abstract "Morphine is an exceptionally effective analgesic whose utility is compromised by the development of tolerance and dependence to the drug. Morphine analgesia and dependence are mediated by its activity at the mu opioid peptide (MOP) receptor [1Matthes H.W. Maldonado R. Simonin F. Valverde O. Slowe S. Kitchen I. Befort K. Dierich A. Le Meur M. Dolle P. et al.Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene.Nature. 1996; 383: 819-823Crossref PubMed Scopus (1407) Google Scholar]. The MOP receptor is activated not only by morphine, but also by other opiate drugs such as methadone and endogenous opioids such as endorphins. Morphine, however, is a unique opioid agonist ligand because it fails to induce endocytic trafficking of the MOP receptor [2Keith D.E. Murray S.R. Zaki P.A. Chu P.C. Lissin D.V. Kang L. Evans C.J. von Zastrow M. Morphine activates opioid receptors without causing their rapid internalization.J. Biol. Chem. 1996; 271: 19021-19024Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar], whereas the endogenous ligands and methadone do facilitate endocytosis [3Keith D.E. Anton B. Murray S.R. Zaki P.A. Chu P.C. Lissin D.V. Monteillet-Agius G. Stewart P.L. Evans C.J. von Zastrow M. mu-Opioid receptor internalization: Opiate drugs have differential effects on a conserved endocytic mechanism in vitro and in the mammalian brain.Mol. Pharmacol. 1998; 53: 377-384Crossref PubMed Scopus (293) Google Scholar]. Using the unique pharmacology of the MOP receptor and its proposed existence as an oligomeric structure [4Jordan B.A. Devi L.A. G-protein-coupled receptor heterodimerization modulates receptor function.Nature. 1999; 399: 697-700Crossref PubMed Scopus (976) Google Scholar], we designed a pharmacological cocktail that facilitates endocytosis of the MOP receptor in response to morphine. This cocktail consists of morphine and a small dose of methadone. Importantly, this cocktail, while retaining full analgesic potency, does not promote morphine dependence. We further demonstrate that dependence is reduced, at least in part, because endocytosis of the MOP receptor in response to morphine prevents the upregulation of N-methyl-D-aspartate (NMDA) receptors." @default.
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• W2022337168 date "2005-06-01" @default.
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• W2022337168 title "An Opiate Cocktail that Reduces Morphine Tolerance and Dependence" @default.
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• W2022337168 doi "https://doi.org/10.1016/j.cub.2005.04.052" @default.
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