Effects of NOP-Related Ligands in Nonhuman Primates

Kiguchi, Norikazu; Ko, Mei‐Chuan

doi:10.1007/164_2019_211

Cited by 19 publications

(14 citation statements)

References 122 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…14 The warm water tail withdrawal assay in non-human primates has been widely used to validate the analgesic effects of opioid-related ligands and to determine their therapeutic windows. 29,30,47 We found that both PZM21 and oxycodone induced full antinociceptive effects with similar durations of action, but PZM21 was 10-fold less potent than oxycodone. All clinically used MOP receptor agonists, including morphine, fentanyl, and buprenorphine, effectively increase primate tail withdrawal latency.…”

Section: Discussionmentioning

confidence: 75%

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 75%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…It produced potent analgesic effects in various rat models of acute and chronic pain 15 , 16 . Although it did not elicit respiratory or motor deficits, or itching, it produced reinforcing effects in nonhuman primates 48 , 49 . Recent clinical studies showed that cebranopadol is effective in treatment of post-operative pain, cancer-related pain, as well as lower back pain 47 , 50 – 52 .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, clinically used buprenorphine which shows partial agonism at both MOP and NOP, has a phosphorylation profile similar to AT-201 wherein it stimulates only S375 phosphorylation at MOP but none at NOP 20 , 21 Cebranopadol showed a more ‘MOP-dominant’ profile and partial to high efficacy at NOP in G protein signaling assays. Despite its clinical efficacy in pain, cebranopadol has been reported to produce reinforcing effects in rats, nonhuman primates and produced drug liking in human clinical trials 48 , 58 , 59 . Correspondingly, it elicited strong multi-site phosphorylation at MOP and weak NOP phosphorylation at S346.…”

Section: Discussionmentioning

confidence: 99%

Attenuated G protein signaling and minimal receptor phosphorylation as a biochemical signature of low side-effect opioid analgesics

Dasgupta

Mann

Polgar

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Multi-receptor targeting has been proposed as a promising strategy for the development of opioid analgesics with fewer side effects. Cebranopadol and AT-121 are prototypical bifunctional ligands targeting the nociceptin/orphanin FQ peptide receptor (NOP) and µ-opioid receptor (MOP) that elicit potent analgesia in humans and nonhuman primates, respectively. Cebranopadol was reported to produce typical MOP-related side effects such as respiratory depression and reward, whereas AT-121 appeared to be devoid of these liabilities. However, the molecular basis underlying different side effect profiles in opioid analgesics remains unknown. Here, we examine agonist-induced receptor phosphorylation and G protein signaling profiles of a series of chemically diverse mixed MOP/NOP agonists, including cebranopadol and AT-121. We found that these compounds produce strikingly different MOP phosphorylation profiles. Cebranopadol, AT-034 and AT-324 stimulated extensive MOP phosphorylation, whereas AT-201 induced selective phosphorylation at S375 only. AT-121, on the other hand, did not promote any detectable MOP phosphorylation. Conversely, none of these compounds was able to elicit strong NOP phosphorylation and low NOP receptor phosphorylation correlated with partial agonism in a GIRK-channel assay. Our results suggest a close correlation between MOP receptor phosphorylation and side effect profile. Thus, bifunctional MOP/NOP opioid ligands combining low efficacy G protein signaling at both NOP and MOP with no detectable receptor phosphorylation appear to be devoid of side-effects such as respiratory depression, abuse liability or tolerance development, as with AT-121.

show abstract

“…Considering the potential ability of intracerebroventricularly administered N/OFQ to attenuate morphine tolerance and suppress drug reinforcing response, the development of new synthetic agonists may constitute an innovative pharmacological approach for analgesics that target both MOP receptor and NOP receptor to enhance their analgesic effect and minimize their side effects as depicted in Figure 2 [ 99 , 101 , 102 , 103 , 104 , 105 ]. Additionally, multiple pathophysiological pathways are involved in the pain process, so developing analgesic agents with multiple mechanisms of actions could be an innovative strategy for developing new effective and safe analgesics [ 106 ].…”

Section: Ligands Of Nop Receptormentioning

confidence: 99%

Spotlight on Nociceptin/Orphanin FQ Receptor in the Treatment of Pain

Daibani

Che

2022

Molecules

View full text Add to dashboard Cite

In our society today, pain has become a main source of strain on most individuals. It is crucial to develop novel treatments against pain while focusing on decreasing their adverse effects. Throughout the extent of development for new pain therapies, the nociceptin/orphanin FQ receptor (NOP receptor) has appeared to be an encouraging focal point. Concentrating on NOP receptor to treat chronic pain with limited range of unwanted effects serves as a suitable alternative to prototypical opioid morphine that could potentially lead to life-threatening effects caused by respiratory depression in overdose, as well as generate abuse and addiction. In addition to these harmful effects, the uprising opioid epidemic is responsible for becoming one of the most disastrous public health issues in the US. In this article, the contributing molecular and cellular structure in controlling the cellular trafficking of NOP receptor and studies that support the role of NOP receptor and its ligands in pain management are reviewed.

show abstract

Effects of NOP-Related Ligands in Nonhuman Primates

Cited by 19 publications

References 122 publications

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

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

Attenuated G protein signaling and minimal receptor phosphorylation as a biochemical signature of low side-effect opioid analgesics

Spotlight on Nociceptin/Orphanin FQ Receptor in the Treatment of Pain

Contact Info

Product

Resources

About