Abstract
Cebranopadol (trans‐6′‐fluoro‐4′,9′‐dihydro‐N,N‐dimethyl‐4‐phenyl‐spiro[cyclohexane‐1,1′(3′H)‐pyrano[3,4‐b]indol]‐4‐amine) is a novel analgesic nociceptin/orphanin FQ opioid peptide (NOP) and classical opioid receptor (MOP, DOP, and KOP) agonist with highly efficacious and potent activity in a broad range of rodent models of nociceptive, inflammatory, and neuropathic pain as well as limited opioid‐type side effects such as respiratory depression. This study was designed to explore contribution and interaction of NOP and classical opioid receptor agonist components to cebranopadol analgesia in the rat spinal nerve ligation (SNL) model. Assessing antihypersensitive activity in SNL rats intraperitoneal (IP) administration of cebranopadol resulted in ED 50 values of 3.3 and 3.58 μg/kg in two independent experiments. Pretreatment (IP) with J‐113397 (4.64 mg/kg) a selective antagonist for the NOP receptor or naloxone (1 mg/kg), naltrindole (10 mg/kg), or nor‐BNI (10 mg/kg), selective antagonists for MOP, DOP, and KOP receptors, yielded ED 50 values of 14.1, 16.9, 17.3, and 15 μg/kg, respectively. This 4‐5 fold rightward shift of the dose‐response curves suggested agonistic contribution of all four receptors to the analgesic activity of cebranopadol. Combined pretreatment with a mixture of the antagonists for the three classical opioid receptors resulted in an 18‐fold potency shift with an ED 50 of 65.5 μg/kg. The concept of dose equivalence was used to calculate the expected additive effects of the parent compound for NOP and opioid receptor contribution and to compare them with the observed effects, respectively. This analysis revealed a statistically significant difference between the expected additive and the observed effects suggesting intrinsic synergistic analgesic interaction of the NOP and the classical opioid receptor components of cebranopadol. Together with the observation of limited respiratory depression in rats and humans the synergistic interaction of NOP and classical opioid receptor components in analgesia described in the current study may contribute to the favorable therapeutic index of cebranopadol observed in clinical trials.
Highlights
Cebranopadol is a first‐in‐class analgesic with agonistic activity at the nociceptin/orphanin FQ opioid peptide (NOP) receptor and the classical μ‐opioid peptide (MOP), κ‐opioid peptide (KOP), and δ‐ opioid peptide (DOP) receptors.[1,2] It has subnanomolar affinity for the human and rat NOP and MOP receptors and low nanomolar affinity for the kappa opioid peptide (KOP) and delta opioid peptide (DOP) receptors.[2]
We demonstrated that equianalgesic doses of cebranopadol produced less respiratory depression than fentanyl because the NOP receptor agonistic component of cebranopadol exerted a protective role by intrinsically counteracting MOP receptor‐mediated respiratory depression in rats.[3]
For each dose of cebranopadol, the paired expected effects associated with the effect ENOP mediated by NOP receptor agonism, and the effect Eopioid mediated by opioid receptor agonism were calculated according to the following equations: ENOP
Summary
Cebranopadol is a first‐in‐class analgesic with agonistic activity at the nociceptin/orphanin FQ opioid peptide (NOP) receptor and the classical μ‐opioid peptide (MOP), κ‐opioid peptide (KOP), and δ‐ opioid peptide (DOP) receptors.[1,2] It has subnanomolar affinity for the human and rat NOP and MOP receptors and low nanomolar affinity for the KOP and DOP receptors.[2]. Activation of both NOP and MOP receptors contributed to antihypersensitive activity of cebranopadol in rat models of spinal nerve ligation (SNL)‐induced mono‐neuropathic pain[2] and complete Freund's adjuvant (CFA)‐induced knee joint arthritis.[4] Interestingly, and unlike morphine, cebranopadol was about 10‐fold more potent in rodent models of chronic neuropathic[2,5] or persistent pain[6] as compared to other more acute pain conditions This increase in potency in neuropathic pain models might be a result of functional NOP receptor upregulation at peripheral,[7,8,9] spinal[8], and supraspinal[10] levels combined with synergistic interaction of activation of NOP and the classical opioid receptors, recent data discuss alternative contribution of the endogenous NOP system and a potential role of spinal interneurons.[11] While agonistic activity at all four opioid receptors contribute to the in vitro profile of cebranopadol and NOP and MOP receptor‐mediated analgesic efficacies have been proven in neuropathic[2] and inflammatory pain models[4] in rodents, neither DOP nor KOP contributions have been assessed in vivo. The aim of the present study was to further characterize the mode of action of cebranopadol in SNL rats by exploring the role of DOP and KOP receptors and to elucidate the way activation of NOP and classical opioid receptors interact to produce antihypersensitivity
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