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Nociceptin Receptor-Related Agonists as Safe and Non-addictive Analgesics

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Abstract

As clinical use of currently available opioid analgesics is often impeded by dose-limiting adverse effects, such as abuse liability and respiratory depression, new approaches have been pursued to develop safe, effective, and non-addictive pain medications. After the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor more than 25 years ago, NOP receptor-related agonists have emerged as a promising target for developing novel and effective opioids that modulate the analgesic and addictive properties of mu-opioid peptide (MOP) receptor agonists. In this review, we highlight the effects of the NOP receptor-related agonists compared with those of MOP receptor agonists in experimental rodent and more translational non-human primate (NHP) models and the development status of key NOP receptor-related agonists as potential safe and non-addictive analgesics. Several lines of evidence demonstrated that peptidic and non-peptidic NOP receptor agonists produce potent analgesic effects by intrathecal delivery in NHPs. Moreover, mixed NOP/MOP receptor partial agonists (e.g., BU08028, BU10038, and AT-121) display potent analgesic effects when administered intrathecally or systemically, without eliciting adverse effects, such as respiratory depression, itch behavior, and signs of abuse liability. More importantly, cebranopadol, a mixed NOP/opioid receptor agonist with full efficacy at NOP and MOP receptors, produces robust analgesic efficacy with reduced adverse effects, conferring promising outcomes in clinical studies. A balanced coactivation of NOP and MOP receptors is a strategy that warrants further exploration and refinement for the development of novel analgesics with a safer and effective profile.

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  1. Huiping Ding and Norikazu Kiguchi have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Huiping Ding & Mei-Chuan Ko

  2. Department of Physiological Sciences, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, 640-8156, Japan

    Norikazu Kiguchi

  3. Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    MaryBeth Dobbins & E. Alfonso Romero-Sandoval

  4. Faculty of Wakayama Health Care Sciences, Takarazuka University of Medical and Health Care, Wakayama, 640-8392, Japan

    Shiroh Kishioka

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Ding, H., Kiguchi, N., Dobbins, M. et al. Nociceptin Receptor-Related Agonists as Safe and Non-addictive Analgesics. Drugs 83, 771–793 (2023). https://doi.org/10.1007/s40265-023-01878-5

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