Morphine has been the prime analgesic for the treatment of severe to moderate pain for centuries. Next to morphine, opioid ligands such as the fentanyl family of painkillers are commonly used in a clinical context. Despite the severe drawbacks that are associated with these analgesics, they remain in use to date. The side effect of tolerance, more specifically, can be ascribed to the activation of an anti-opioid system involving the increased production of “anti-opioids”. In consequence, the long-duration efficiency of opioids is challenged and these analgesics lose their effect over time. To overcome drawbacks inherent to opioids one can design single molecules that interact with multiple targets, also called designed multiple ligands (DMLs). Previously, we developed an opioid-neurokinin 1 peptidomimetic, Dmt-DArg-Aba-Gly-NMe-3',5'-(CF3)2-Bn.1 This compound is characterized by overlapping opioid and neurokinin pharmacophores and, gratifyingly, the fusion of these pharmacophores preserved the desired binding to NK1R and opioid receptors. Although this compound alleviated acute pain after intravenous injection, analgesic tolerance emerged after repetitive administrations. Hence, we pursued our efforts and various structural modifications were performed to determine the key features for NK1R binding and antagonism.2 As such, Dmt-D-Arg-Aba-beta-Ala-NMe-Bn was identified as a promising hybrid. Both the lead ligand and this novel hybrid were subjected to acute and neuropathic pain models in rats. Compared to the parent opioid compounds, the hybrid structures were more active in the neuropathic pain models. Even though potent analgesic effects were observed for both chimeras, upon chronic administration, they manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rats. The above ligands are representatives of balanced and high opioid/lower NK1R activity, respectively. They can serve as general analgesics, able to attenuate acute and neuropathic pain, but tolerance and cross-tolerance with morphine were still detected. In order to verify whether an inverted profile, i.e. high NK1R/lower opioid activity, would be beneficial, we designed fused ligands that possess lower opioid activity and high NK1R binding and antagonism. To our delight, two of these ligands gave way to decreased tolerance in the antihyperalgesic cold plate model and diminished cross tolerance with morphine.