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Cellular Adaptations Induced during Morphine Tolerance Recent promising approaches to limit tolerance have been extensively reviewed and include simultaneous activation of more than one opioid receptor type (e.g., MOR and DOR receptors), selective targeting of hetero-oligomers, or opioids that differentially activate distinct intracellular signaling cascades, possibly involving differential activation of G subtypes (Pieyro and Archer-Lahlou, 2007), and particularly differential G protein activation versus endocytosis (Martini and Whistler, 2007