title: Pharmacological characterization of cebranopadol a novel analgesic acting as mixed nociceptin/orphanin FQ and opioid receptor agonist.
abstract: The aim of the study was to investigate the in vitro and in vivo pharmacological profile of cebranopadol, a novel agonist for opioid and nociceptin/orphanin FQ (N/OFQ) receptors (NOP). In vitro cebranopadol was assayed in calcium mobilization studies in cells coexpressing NOP or opioid receptors and chimeric G-proteins and in a bioluminescence resonance energy transfer (BRET) assay for studying receptor interaction with G-protein andβ-arrestin 2. The mouse tail withdrawal and formalin tests were used for investigating cebranopadol antinociceptive properties. In calcium mobilization studies cebranopadol showed the following rank order of potency NOP = mu > kappa ≥ delta. In BRET studies, cebranopadol promoted NOP and mu receptors interaction with G-protein with similar high potency and efficacy. However, cebranopadol did not stimulated NOP-β-arrestin 2 interactions and displayed reduced potency at mu/β-arrestin 2. In vivo, cebranopadol exhibits highly potent and extremely long-lasting antinociceptive effects. The effects of cebranopadol in the tail withdrawal assay were sensitive to both SB-612111 and naloxone. Collectively the present results confirm and extend previous finding demonstrating that cebranopadol, by acting as mixed NOP/opioid receptor agonist, elicits robust analgesic effects in different pain models.
authors.affiliation: Department of Medical Sciences Section of Pharmacology and National Institute of Neuroscience University of Ferrara Ferrara Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rizzi
authors.affiliation: Department of Medical Sciences Section of Pharmacology and National Institute of Neuroscience University of Ferrara Ferrara Italy.
authors.forename: Maria Camilla
authors.initials: MC
authors.lastname: Cerlesi
authors.affiliation: Department of Medical Sciences Section of Pharmacology and National Institute of Neuroscience University of Ferrara Ferrara Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ruzza
authors.affiliation: Department of Medical Sciences Section of Pharmacology and National Institute of Neuroscience University of Ferrara Ferrara Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Malfacini
authors.affiliation: Department of Medical Sciences Section of Pharmacology and National Institute of Neuroscience University of Ferrara Ferrara Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrari
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA University of Ferrara Ferrara Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bianco
authors.affiliation: Department of Pharmacology Istituto Superiore di Sanita' Rome Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Costa
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA University of Ferrara Ferrara Italy.
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA University of Ferrara Ferrara Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.affiliation: Department of Medical Sciences Section of Pharmacology and National Institute of Neuroscience University of Ferrara Ferrara Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo'
keywords: Biased agonism; NOP receptor; bioluminescence resonance energy transfer; calcium mobilization; cebranopadol; formalin test; opioid receptors; pain; tail withdrawal