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Introduction: Mu-opioid receptors (MORs) are G-coupled protein receptors with a high affinity for both endogenous and exogenous opioids. MORs are widely expressed in the central nervous system (CNS), peripheral organs, and the immune system. They mediate pain and reward and have been implicated in the pathophysiology of opioid, cocaine, and other substance use disorders. Using the long axial field-of-view (LAFOV) PennPET Explorer instrument and the MOR selective radioligand [ Methods: Six female and seven male healthy subjects underwent two [ Results: Naloxone blockade reduced MOR availability by 40-50% in the caudate, putamen, thalamus, amygdala, and ventral tegmentum, brain regions known to express high levels of MORs. Women showed greater receptor occupancy in the thalamus, amygdala, hippocampus and frontal and temporal lobes and a greater naloxone-induced reduction in thalamic MOR availability than men (p's <0.05). For determining brain MOR availability, there was less variance in the visual cortex than the occipital cortex reference region. For peripheral MOR determination, the descending aorta reference region showed less variance than the extremity muscle, but both showed blocking effects of naloxone. Conclusions: [