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Whereas in vitro experiments showed that S375 is phosphorylated by GRK5 upon morphine exposure (Doll et al., 2012) and S375 phosphorylation plays a major role in MOR desensitization (Schulz et al., 2004), S375A knock-in mice still present anti-nociceptive tolerance upon acute and chronic exposure to morphine (Grecksch et al., 2011)