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Potential innovative targets in the treatment of pain: Combined μ and NOP receptor agonists

Raphael J. Leo, MA, MD


Opioid analgesics are potent and widely used medications employed to manage moderate-to-severe acute pain; their utility in the management of chronic inflammatory and neuropathic pain is modest and is beset with adverse effects and concerns related to abuse and addiction. The discovery of the nonclassical opioid, ie, the nociception/orphanin receptor (NOP), has sparked interest into another possible analgesic target. Preclinical studies have demonstrated pain mitigating effects associated with NOP receptor activation while simultaneously reducing conventional μ-opioid-related adverse and euphoric effects. Consequently, agents possessing dual agonism of both μ and NOP receptor activations present an innovative and promising potential target for pain management.


opioid receptors nociceptin/orphanin receptor analgesia

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Dowell D, Haegerich TM, Chou R: CDC guideline for prescribing opioids for chronic pain–United States, 2016. JAMA. 2016; 315(15): 1624-1645. PMID: 26977696.

Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US): Facing Addiction in America: The Surgeon General's Spotlight on Opioids [Internet]. Washington, DC: US Department of Health and Human Services, 2018. PMID: 30860690.

Günther T, Dasgupta P, Mann A, et al.: Targeting multiple opioid receptors—Improved analgesics with reduced side effects? Br J Pharmacol. 2018; 175(14): 2857-2868. PMID: 28378462.

Busse JW, Wang L, Kamaleldin M, et al.: Opioids for chronic noncancer pain: A systematic review and meta-analysis. JAMA. 2018; 320(23): 2448-2460. PMID: 30561481.

Rosenblum A, Marsch LA, Joseph H, et al.: Opioids and the treatment of chronic pain: Controversies, current status, and future directions. Exp Clin Psychopharmacol. 2008; 16(5): 405-416. DOI: 10.1037/a0013628.

Guy GP Jr, Zhang K, Bohm MK, et al.: Vital signs: Changes in opioid prescribing in the United States, 2006-2015. MMWR Morb Mortal Wkly Rep. 2017; 66(26): 697-704. PMID: 28683056.

Chan BK, Tam LK, Wat CY, et al.: Opioids in chronic noncancer pain. Expert Opin Pharmacother. 2011; 12: 705-720.

Manchikanti L, Ailinani H, Koyyalagunta D, et al.: A systematic review of randomized trials of long-term opioid management for chronic non-cancer pain. Pain Phys. 2011; 14(2): 91-121.

McNicol E: Opioid side effects and their treatment in patients with chronic cancer and noncancer pain. J Pain Palliat Care Pharmacother. 2008; 22(4): 270-281. PMID: 21923311.

Lambert DG: The nociceptin/orphanin FQ receptor: A target with broad therapeutic potential. Nat Rev Drug Discov. 2008; 7(8): 694-710. PMID: 18670432.

Donica CL, Awwad HO, Thakker DR, et al.: Cellular mechanisms of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor regulation and heterologous regulation by N/OFQ. Mol Pharmacol. 2013; 83(5): 907-918. PMCID: PMC3629824

Kiguchi N, Ding H, Kishioka S, et al.: Nociceptin/orphanin FQ peptide receptor-related ligands as novel analgesics. CTMC. 2020; 20(31): 2878-2888. PMID: 32384033.

Raffa RB, Burdge G, Gambrah J, et al.: Cebranopadol: Novel dual opioid/NOP receptor agonist analgesic. J Clin Pharm Ther. 2017; 42(1): 8-17. PMID: 27778406.

Monteillet-Agius G, Fein J, Anton B, et al.: ORL-1 and mu opioid receptor antisera label different fibers in areas involved in pain processing. J Comp Neurol. 1998; 399(3): 373-383. PMID: 9733084.

Liu Z, Wang Y, Zhang J, et al.: Orphanin FQ: An endogenous antagonist of rat brain dopamine transporter. NeuroReport. 2001; 12(4): 699-702. PMID: 11277567.

Murphy NP, Maidment NT: Orphanin FQ/nociceptin modulation of mesolimbic dopamine transmission determined by microdialysis. J Neurochem. 2002; 73: 179-186. PMID: 10386969.

Kiguchi N, Ding H, Ko MC: Central N/OFQ-NOP receptor system in pain modulation. Adv Pharmacol. 2016; 75: 217-243. PMID: 26920014.

Ko MC, Naughton NN: Antinociceptive effects of nociceptin/orphanin FQ administered intrathecally in monkeys. J Pain. 2009; 10(5): 509-516. PMID: 19231294.

Hu E, Cal G, Guerrini R, et al.: Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112. Pain. 2010; 148(1): 107-113. DOI: 10.1016/j.pain.2009.10.026. PMID: 19945794.

Ko MC, Woods JH, Fantegrossi WE, et al.: Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys. Neuropsychopharmacology. 2009; 34(9): 2088-2096. PMID: 19279568.

Schröder W, Lambert DG, Ko MC, et al.: Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br J Pharmacol. 2014; 171(16): 3777-3800. DOI: 10.1111/bph.12744.

Linz K, Christoph T, Tzschentke TM, et al.: Cebranopadol: A novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014; 349(3): 535-548. PMID: 24713140.

Sukhtankar DD, Lee H, Rice KC, et al.: Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain. Psychopharmacology (Berl.). 2014; 231(7): 1377-1387. PMID: 24217900.

Podlesnik CA, Ko MC, Winger G, et al.: The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys. Psychopharmacology (Berl.). 2011; 213: 53-60. PMID: 20852848.

Rutten K, De Vry J, Bruckmann W, et al.: Effects of the NOP receptor agonist Ro65-6570 on the acquisition of opiate- and psychostimulant induced conditioned place preference in rats. Eur J Pharmacol. 2010; 645: 119-126.

Toll L: The use of bifunctional NOP/mu and NOP receptor selective compounds for the treatment of pain, drug abuse, and psychiatric disorders. Curr Pharm Des. 2013; 19: 7451-7460. PMID: 23448477.

Murphy NP: Nociceptin/orphanin FQ, hedonic state and the response to abused drugs. Nihon Shinkei Seishin Yakurigaku Zasshi. 2004; 24(5): 295-298. PMID: 15658507.

Murphy NP, Ly HT, Maidment NT: Intracerebroventricular orphanin FQ/nociceptin suppresses dopamine release in the nucleus accumbens of anaesthetized rats. Neuroscience. 1996; 75(1): 1-4. PMID: 8923516.

Ciccocioppo R, Angeletti S, Sanna PP, et al.: Effect of nociceptin/orphanin FQ on the rewarding properties of morphine. Eur J Pharmacol. 2000; 404: 153-159.

Journigan VB, Polgar WE, Khroyan TV, et al.: Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP-receptor selective scaffolds. Part II. Bloorg Med Chem. 2014; 22(8): 2508-2516. PMID: 24657054.

Lin AP, Ko MC: The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS Chem Neurosci. 2013; 4(2): 214-224. PMID: 23421672.

Ruzza C, Holanda VA, Gavioli EC, et al.: NOP agonist action of cebranopadol counteracts its liability to promote physical dependence. Peptides. 2019; 112: 101-105. PMID: 30550769.

Kotlin´ska J, Suder P, Legowska A, et al.: Orphanin FQ/nociception inhibits morphine withdrawal. Life Sci. 2000; 66(8): PL119-PL123. PMID: 10680585.

Ding H, Kiguchi N, Yasuda D, et al.: A bifunctional nociception and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med. 2018; 10(456): eaar3483. PMID: 30158150.

Ding H, Czoty PW, Kiguchi N, et al.: A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. Proc Natl Acad Sci USA. 2016; 113(37): E5511-E5518. PMID: 27573832.

Kiguchi N, Ding H, Cami-Kobeci G, et al.: BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates. Br J Anaesth. 2019; 122(6): e146-e156. PMID: 30916003.

Adeghate E, Fehér E, Kalász H: Evaluating the phase II drugs currently under investigation for diabetic neuropathy. Expert Opin Investig Drugs. 2015; 24(1): 1-15. DOI: 10.1517/13543784.2014.954033. PMID: 25171371.

Lambert DG, Bird MF, Rowbotham DJ: Cebranopadol: A first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. Br J Anaesth. 2015; 114(3): 364-366. PMID: 25248647.

Raffa RB: On subclasses of opioid analgesics. Curr Med Res Opin. 2014; 30(12): 2579-2584.

Koch ED, Kapanadze S, Eerdekens MH, et al.: Cebranopadol, a novel first-in-class analgesic drug candidate: First experience with cancer-related pain for up to 26 weeks. J Pain Symptom Manage. 2019; 58(3): 390-399.

Scholz A, Bothmer J, Kok M, et al.: Cebranopadol: A novel, first-in-class, strong analgesic: Results from a randomized phase IIa clinical trial in postoperative acute pain. Pain Phys. 2018; 1: E193-E205.

A randomized 4-week Phase IIa trial evaluating the efficacy, safety, and tolerability of GRT6005, a new centrally acting analgesic, in subjects with moderate to severe pain due to osteoarthritis (OA) of the knee. 2012. Identification No. NCT01357837. Available at Accessed February 21, 2021.

Christoph A, Eerdekens MH, Kok M, et al.: Cebranopadol, a novel first-in-class analgesic drug candidate: First experience in patients with chronic low back pain in a randomized clinical trial. Pain J. 2017; 158(9): 1813-1824. PMID: 28644196.

A randomized 4-week Phase IIa trial evaluating the efficacy, safety, and tolerability of GRT6005, a new centrally acting analgesic, in subjects with pain due to diabetic polyneuropathy. 2012. Identification No. NCT01347671. Available at Accessed February 21, 2021.

A randomized Phase IIa trial evaluating the safety and efficacy of a new centrally acting analgesic in subjects with pain due to diabetic polyneuropathy. 2011. Identification No. NCT00878293. Available at Accessed February 21, 2021.

Eerdekens MH, Kapanadze S, Koch ED, et al.: Cancer-related chronic pain: Investigation of the novel analgesic drug candidate cebranopadol in a randomized, double-blind, noninferiority trial. Eur J Pain. 2019; 23: 577-588. PMID: 30365202.

Dahan A, Boom M, Sarton E, et al.: Respiratory effects of the nociceptin/orphanin FQ peptide and opioid receptor agonist, cebranopadol, in healthy human volunteers. Anesthesiology. 2017; 126(4): 697-707. PMID: 28291085.

Göhler K, Sokolowska M, Schoedel KA, et al.: Assessment of the abuse potential of cebranopadol in nondependent recreational opioid users: A phase 1 randomized controlled study. J Clin Psychopharmacol. 2019; 39(1): 46-56. PMID: 30531478.



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