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Preclinical work has demonstrated that activation of mu opioid receptors (MORs) is necessary, but not sufficient for ketamine to reduce depressive-like behaviors 17 , that ( S )-ketamine involves direct interactions with brain MORs at doses and concentrations relevant to its reinforcement and antidepressant-like efficacy 18 , and that -endorphin presence and opioid receptor activation in the mPFC may be required for ketamines antidepressant actions 19