However, atomoxetine, a monoamine reuptake inhibitor that engages more NET than SERT, exhibited synergy with morphine at doses that yielded significant NET occupancy and modest SERT occupancy. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of CNS transporter occupancy potentiated the CBR 5884 antinociceptive response to morphine. In contrast, duloxetine, a monoamine reuptake inhibitor that engages more SERT than NET, did not exhibit antinociceptive synergy with morphine at a dose which produced comparable NET and near-maximal occupancy of SERT. Thus, monoamine reuptake inhibitor and morphinemediated antinociceptive synergy requires dual engagement of both NE and 5-HT transporters, but excessive SERT occupancy may mask the synergistic interactions between these antinociceptive systems. To our knowledge, these results represent the first quantitative demonstration that the balance between NET and SERT inhibition for a parenterally administrated monoamine reuptake inhibitor can influence the synergistic interaction with morphine in the rat formalin model. Our findings are consistent with numerous other studies that have reported synergy and/or additivity between morphine and agents that AM 4668 modulate 5-HT or NE pathways. Preclinically, in addition to the rat formalin model, synergistic interactions between monoamine reuptake inhibitors and morphine have also been observed in mouse tail-flick, rat thermal paw withdrawal and in preclinical pain models of postoperative pain. Recently, Schroder et. al. demonstrated a synergistic interaction between NET inhibition and m-receptor agonism in the low-intensity tail-flick and spinal nerve ligation rat models based on isobolographic analysis of estimated receptor/transporter occupancy for tapentadol. The predicted antinociceptive synergy with the dual mechanism tapentadol contrasts with our – conclusion that modest SERT engagement is required for antinociceptive synergy with morphine. The conflicting results could reflect different occupancy requirements in the rat formalin model compared with other models. It is also possible that the isobolographic analysis based on occupancy estimates calculated from tapentadol��s brain concentration could yield a different interpretation than one based on direct ex vivo occupancy measurements from rats monitored for nociceptive behavior, as in our current study. In clinical settings, desipramine, a TCA that inhibits NET preferentially over SERT, enhances morphine analgesia in post-operative dental pain patients. However, the clinical reports that duloxetine can reduce morphine consumption in both acute and chronic pain populations appear to be at odds with our preclinical finding of a lack of synergy between duloxetine and morphine and are worthy of further discussion.