• Chiara Ruzza, Victor A Holanda, Elaine C Gavioli, Claudio Trapella, and Girolamo Calo.
• Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
• Peptides. 2019 Feb 1; 112: 101-105.

AbstractCebranopadol is a mixed NOP/opioid receptor agonist currently under development as innovative analgesic. In this study the liability of cebranopadol to produce opioid-type physical dependence has been evaluated in comparison with morphine in wild type mice and in mice knockout for the NOP receptor gene (NOP(-/-)). Mice were treated twice a day for 5 days with increasing doses of cebranopadol or morphine (cumulative doses 10.2 and 255 mg/kg, respectively) and the number of jumping in response to naloxone 10 mg/kg were measured after 2 h from the last injection. In wild type mice naloxone evoked a similar withdrawal jumping behavior in animal pretreated with morphine or cebranopadol. In NOP(-/-) mice morphine treatment produced the same signs of withdrawal as in NOP(+/+) animals, while cebranopadol treatment elicited a stronger withdrawal syndrome in NOP(-/-) than of NOP(+/+) mice. These results demonstrated that the activation of the NOP receptor reduces the liability of cebranopadol to produce opioid-like physical dependence. Thus, the simultaneous activation of NOP and opioid receptors can be an effective pharmacological strategy to counteract physical dependence to opioid drugs.Copyright © 2018 Elsevier Inc. All rights reserved.

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