Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking.

Maria Dumitrascuta,Olga Trovato,Gerhard Wolber,Marcel Bermudez,Mariana Spetea,Steven Ballet,Jolien De Neve

doi:10.3390/molecules26113267

Abstract

Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund’s adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.

Highlights

We further investigated the in vivo effects of KGNOP1 in mouse models of acute and chronic inflammatory pain after subcutaneous (s.c.) administration and assessed potential opioid liabilities for locomotor dysfunction and rewarding and withdrawal effects after chronic treatment, in comparison to the clinically relevant morphine
We re-evaluated the binding properties of KGNOP1 to the human MOR, DOR, KOR, and NOP receptors by radioligand binding to membrane preparations from Chinese hamster ovary (CHO) cells overexpressing recombinant receptors, as described previously [26,27] (Figure 1A)
KGNOP1 bound to the NOP receptor (Ki = 141 nM), with reduced affinity in comparison with the other opioid receptors, as determined in competitive radioligand binding assays, and aligned with previously reported data [22]

Summary

Introduction

Chronic pain, remains an unmet medical need at the beginning of the 21st century. While opioid-based pharmacotherapy is still the most powerful strategy for the treatment of moderate to severe pain, the risk–benefit ratio is suboptimal because of frequent and serious side effects [1]. The majority of clinically used opioids are agonists to the MOR, and these are vastly misused and abused [1]. Alternative chemical and pharmacological strategies are evaluated to mitigate the deleterious effects of opioids, amongst which are multifunctional ligands, G protein-biased agonists, peripherally restricted opioids, and abuse-deterrent formulations of existing opioids [6,7,8,9,10]

Methods

Results

Discussion

Conclusion