A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates

Ding, Huiping; Kiguchi, Norikazu; Yasuda, Dennis; Daga, Pankaj; Polgar, Willma E.; Lu, James; Czoty, Paul W.; Kishioka, Shiroh; Zaveri, Nurulain T.; Ko, Mei‐Chuan

doi:10.1126/scitranslmed.aar3483

Cited by 106 publications

(122 citation statements)

References 78 publications

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“…After longterm exposure (i.e., 4 weeks), morphine-treated primates developed tolerance to antinociceptive effects of morphine. 42 In contrast, BU10038-treated primates did not show tolerance by either systemic or intrathecal route, even after 4 weeks of chronic administration. Although more frequent dosing and longer durations of treatment could result in tolerance, these findings may indicate that bifunctional MOP/NOP agonists like BU10038 have advantages over morphine in repeated or chronic dosing regimens.…”

Section: Discussionmentioning

confidence: 92%

“…40 41 Following a long-term exposure to systemic morphine (i.e., 2 injections of 1.8 mg kg -1 daily for 4 weeks), morphine-treated monkeys developed tolerance to antinociception. 42 In the same group of animals, following the same duration of chronic administration, BU10038 (0.01 mg kg -1 , i.m. )-treated monkeys did not show tolerance to antinociception produced by 0.003 and 0.01 mg kg -1 (Fig.…”

Section: Chronic Exposure To Bu10038 Does Not Cause Tolerancementioning

confidence: 99%

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BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates

Kiguchi

Ding

Cami‐Kobeci

et al. 2019

British Journal of Anaesthesia

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BACKGROUND: The marked increase in misuse and abuse of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. METHODS: A series of behavioral and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. RESULTS: Following systemic administration, BU10038 (0.001-0.01 mg kg -1 ) dosedependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e., little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10-30 fold higher dose (0.01-0.1 mg kg -1 ). Following intrathecal administration, BU10038 (3 μg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. CONCLUSIONS: These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists like BU10038 as a safe, non-addictive

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Section: Discussionmentioning

confidence: 92%

Section: Chronic Exposure To Bu10038 Does Not Cause Tolerancementioning

confidence: 99%

BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates

Kiguchi

Ding

Cami‐Kobeci

et al. 2019

British Journal of Anaesthesia

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“…NOP receptors and N/OFQ play an active role in pain transmission, and a mixed NOP receptor/MOR agonist is now in clinical trials, and selective NOP receptor agonists are examined as possible analgesics, although they are often very sedative [ 117 ]. Notable exemptions are cebranopadol and AT-121, perhaps due to ligand bias, although we were unable to locate a bias factor for the latter in the literature [ 118 , 119 ]. NOP receptor agonists are more effective in blocking chronic than acute pain for unknown reasons.…”

Section: Biased Agonism On Nop Receptormentioning

confidence: 99%

Biased Opioid Ligands

2020

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Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

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“…Astraea Therapeutics' AT121 falls into this last category. 3 It is targeted at two different opioid receptors -the mu-opioid receptor and the nociceptin receptor. Most opioid medicines are mu-agonists; Astraea claims that nociceptin can modulate pain in the same way morphine can, without its rewarding properties or tendency to build up tolerance.…”

Section: Alternative Opioidsmentioning

confidence: 99%