Mixed mu-nociceptin/orphanin FQ opioid receptor agonists and the search for the analgesic holy grail

Opioids targeting mu;μ (MOP) receptors produce analgesia in the peri-operative period and palliative care. They also produce side effects including respiratory depression, tolerance/dependence and addiction. The N/OFQ opioid receptor (NOP) also produces analgesia but is devoid of the major MOP side effects. Evidence exists for MOP-NOP interaction and mixed MOP-NOP ligands produce analgesia with reduced side effects. We have generated a HEKMOP/NOP human expression system and used bivalent MOP-NOP and fluorescent ligands to (i) probe for receptor interaction and (ii) consequences of that interaction. We used HEKMOP/NOP cells and two bivalent ligands; Dermorphin-N/OFQ (MOP agonist-NOP agonist; DeNO) and Dermorphin-UFP101 (MOP agonist-NOP antagonist; De101). We have determined receptor binding profiles, GTPγ[35S] binding, cAMP formation and ERK1/2 activation. We have also probed MOP and NOP receptor interactions in HEK cells and hippocampal neurones using the novel MOP fluorescent ligand, DermorphinATTO488 and the NOP fluorescent ligand N/OFQATTO594. In HEKMOP/NOP MOP ligands displaced NOP binding and NOP ligands displaced MOP binding. Using fluorescent probes in HEKMOP/NOP cells we demonstrated MOP-NOP probe overlap and a FRET signal indicating co-localisation. MOP-NOP were also co-localised in hippocampal tissue. In GTPγ[35S] and cAMP assays NOP stimulation shifted the response to MOP rightwards. At ERK1/2 the response to bivalent ligands generally peaked later. We provide evidence for MOP-NOP interaction in recombinant and native tissue. NOP activation reduces responsiveness of MOP activation; this was shown with conventional and bivalent ligands.

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“…This complements data with MOP-NOP ligands BU08028 [25] and AT-121 [26]. Cebranopadol is being evaluated in clinical trials [27][28][29].…”

Section: Introductionsupporting

confidence: 58%

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands

et al. 2022

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“…5 Mounting evidence strongly suggests that the coactivation of the nociceptin and μ receptors might provide synergistic analgesic effects and simultaneously counteract μ receptor-mediated side effects. [6][7][8][9][10] Mixed nociceptin/μ receptor agonists are currently being pursued as promising novel analgesics.Several mixed nociceptin/μ receptor agonists have been reported. BU08028 and BU10038 bind with reasonable…”

mentioning

confidence: 99%

Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates

Ding¹,

Trapella²,

Kiguchi³

et al. 2021

Anesthesiology

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Background Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates. Methods The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with μ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. Results Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] μg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] μg/kg). Pretreatment with antagonists selective for nociceptin and μ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose–response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 μg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 μg; 3,009 ± 1,474 scratches). Conclusions In nonhuman primates, the μ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/μ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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“…Other chemical strategies may provide promising alternatives. 7,8 For example ligands with mixed agonist activities do not induce respiratory depression or reinforcing effects. 31,37,42 Pharmacological studies using nonhuman primate models will continue to advance our understanding of receptor functions and drug effects, and provide translational relevance in the development of effective medications to treat pain and substance abuse.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Therefore, research into non-addictive analgesics is critical. Among research strategies 7,8 to mitigate MOP receptor-mediated adverse effects, the development of 'biased' ligands has emerged. 8,9 MOP receptor activation drives at least two major different signalling pathways: G-protein signalling and b-arrestin recruitment.…”

mentioning

confidence: 99%

Antinociceptive, reinforcing, and pruritic effects of the G-protein signalling-biased mu opioid receptor agonist PZM21 in non-human primates

Ding

Kiguchi

Perrey

et al. 2020

British Journal of Anaesthesia

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Background: A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent G i/o activator with minimal b-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown. The aim of this study was to investigate PZM21 actions after systemic or intrathecal administration in primates. Methods: Antinociceptive, reinforcing, and pruritic effects of PZM21 were compared with those of the clinically used MOP receptor agonists oxycodone and morphine in assays of acute thermal nociception, capsaicin-induced thermal allodynia, itch scratching responses, and drug self-administration in gonadally intact, adult rhesus macaques (10 males, six females). Results: After subcutaneous administration, PZM21 (1.0e6.0 mg kg À1 ) and oxycodone (0.1e0.6 mg kg À1 ) induced dosedependent thermal antinociceptive effects (P<0.05); PZM21 was 10 times less potent than oxycodone. PZM21 exerted oxycodone-like reinforcing effects and strength as determined by two operant schedules of reinforcement in the intravenous drug self-administration assay. After intrathecal administration, PZM21 (0.03e0.3 mg) dose-dependently attenuated capsaicin-induced thermal allodynia (P<0.05). Although intrathecal PZM21 and morphine induced MOP receptor-mediated antiallodynic effects, both compounds induced robust, long-lasting itch scratching. Conclusions: PZM21 induced antinociceptive, reinforcing, and pruritic effects similar to clinically used MOP receptor agonists in primates. Although structure-based discovery of PZM21 identified a novel avenue for studying G-protein signalling-biased ligands, biasing an agonist towards G-protein signalling pathways did not determine or alter reinforcing (i.e. abuse potential) or pruritic effects of MOP receptor agonists in a translationally relevant non-human primate model.

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Mixed mu-nociceptin/orphanin FQ opioid receptor agonists and the search for the analgesic holy grail

Cited by 5 publications

References 18 publications

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands

Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates

Antinociceptive, reinforcing, and pruritic effects of the G-protein signalling-biased mu opioid receptor agonist PZM21 in non-human primates

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