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Endogenous opioid and nociceptin systems are widely distributed in the gastrointestinal tract where they seem to play a crucial role in maintaining the intestinal homeostasis. The aim of our study was to assess whether activation of nociceptin (NOP) and µ-opioid (MOP) receptors by a mixed NOP/MOP receptor agonist, BU08070, induces anti-inflammatory response in experimental colitis. The anti-inflammatory effect of BU08070 (1 mg/kg i.p.) was characterized in the mouse model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, based on the assessment of the macroscopic and microscopic total damage scores and determination of myeloperoxidase (MPO) activity and TNF-α level in the colon. The effect of BU08070 on cell viability and NF-κB was characterized in THP-1 Blue cell line. The antinociceptive activity of BU08070 was examined in mustard oil-induced mouse model of abdominal pain. A potent anti-inflammatory effect of BU08070 (1 mg/kg i.p.) was observed as indicated by decrease in macroscopic damage score (1.88±0.39 vs. 5.19±0.43 units in TNBS alone treated mice), MPO activity (2.29±0.37 vs. 9.64±2.55 units) and TNF-α level in the colon (35.85±2.45 vs. 49.79±3.81 pg/ml). The anti-inflammatory effect of BU08070 was reversed by selective NOP and MOP receptor antagonists. BU08070 produced concentration-dependent inhibition of TNF-α and LPS-induced NF-κB activation. BU08070 exerted antinociceptive action in mice with experimental colitis. In conclusion, BU08070 significantly reduced the severity of colitis in TNBS-treated mice compared with controls. These results suggest that BU08070 is a potential therapeutic agent for inflammatory bowel diseases therapy. [ABSTRACT FROM AUTHOR]

Background: Opioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The μ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures. Results: This study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone. Conclusion: Development of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects. [ABSTRACT FROM AUTHOR]