scholarly journals Differential Effects of Nociceptin/Orphanin FQ (NOP) Receptor Agonists in Acute versus Chronic Pain: Studies with Bifunctional NOP/μ Receptor Agonists in the Sciatic Nerve Ligation Chronic Pain Model in Mice

2011 ◽  
Vol 339 (2) ◽  
pp. 687-693 ◽  
Author(s):  
Taline V. Khroyan ◽  
Willma E. Polgar ◽  
Juan Orduna ◽  
Jose Montenegro ◽  
Faming Jiang ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sciatic Nerve ◽  
Nop Receptor ◽  
Orphanin Fq ◽  
Pain Model ◽  
Differential Effects ◽  
Receptor Agonists ◽  
Μ Receptor

Effects of age and size on development of allodynia in a chronic pain model produced by sciatic nerve ligation in rats

Pain ◽  
1992 ◽  
Vol 51 (3) ◽  
pp. 313-316 ◽  
Author(s):  
Erik N. Tanck ◽  
Jeffrey S. Kroin ◽  
Robert J. McCarthy ◽  
Richard D. Penn ◽  
Anthony D. Ivankovich
Keyword(s):  
Chronic Pain ◽  
Sciatic Nerve ◽  
Pain Model

scholarly journals A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

2016 ◽  
Vol 113 (37) ◽  
pp. E5511-E5518 ◽  
Author(s):  
Huiping Ding ◽  
Paul W. Czoty ◽  
Norikazu Kiguchi ◽  
Gerta Cami-Kobeci ◽  
Devki D. Sukhtankar ◽  
...  
Keyword(s):  
Physical Dependence ◽  
Opioid Analgesic ◽  
Opioid Analgesics ◽  
Abuse Liability ◽  
Ratio Schedule ◽  
Tolerability Profile ◽  
Nop Receptor ◽  
Orphanin Fq ◽  
Self Administration ◽  
Receptor Agonists

Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001–0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics.

scholarly journals Agonist-selective NOP receptor phosphorylation correlates in vitro and in vivo and reveals differential post-activation signaling by chemically diverse agonists

2019 ◽  
Vol 12 (574) ◽  
pp. eaau8072 ◽  
Author(s):  
Anika Mann ◽  
Lionel Moulédous ◽  
Carine Froment ◽  
Patrick R. O’Neill ◽  
Pooja Dasgupta ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Nop Receptor ◽  
Orphanin Fq ◽  
Receptor Phosphorylation ◽  
Receptor Agonists ◽  
Differential Signaling ◽  
Receptor Family

Agonists of the nociceptin/orphanin FQ opioid peptide (NOP) receptor, a member of the opioid receptor family, are under active investigation as novel analgesics, but their modes of signaling are less well characterized than those of other members of the opioid receptor family. Therefore, we investigated whether different NOP receptor ligands showed differential signaling or functional selectivity at the NOP receptor. Using newly developed phosphosite-specific antibodies to the NOP receptor, we found that agonist-induced NOP receptor phosphorylation occurred primarily at four carboxyl-terminal serine (Ser) and threonine (Thr) residues, namely, Ser346, Ser351, Thr362, and Ser363, and proceeded with a temporal hierarchy, with Ser346 as the first site of phosphorylation. G protein–coupled receptor kinases 2 and 3 (GRK2/3) cooperated during agonist-induced phosphorylation, which, in turn, facilitated NOP receptor desensitization and internalization. A comparison of structurally distinct NOP receptor agonists revealed dissociation in functional efficacies between G protein–dependent signaling and receptor phosphorylation. Furthermore, in NOP-eGFP and NOP-eYFP mice, NOP receptor agonists induced multisite phosphorylation and internalization in a dose-dependent and agonist-selective manner that could be blocked by specific antagonists. Our study provides new tools to study ligand-activated NOP receptor signaling in vitro and in vivo. Differential agonist-selective NOP receptor phosphorylation by chemically diverse NOP receptor agonists suggests that differential signaling by NOP receptor agonists may play a role in NOP receptor ligand pharmacology.

OLDER, LARGER RATS FAIL TO DEVELOP ALLODYNIA IN A CHRONIC PAIN MODEL OF SCIATIC NERVE LIGATION

1992 ◽  
Vol 77 (Supplement) ◽  
pp. A845
Author(s):  
R J McCarthy ◽  
E N Tanck ◽  
J S Kroin ◽  
R D Penn ◽  
A D Ivankovich
Keyword(s):  
Chronic Pain ◽  
Sciatic Nerve ◽  
Pain Model

scholarly journals Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

2021 ◽  
Author(s):  
Amy Alder
Keyword(s):  
Chronic Pain ◽  
Side Effects ◽  
G Protein ◽  
Respiratory Depression ◽  
Knockout Mice ◽  
Side Effect ◽  
Therapeutic Window ◽  
Receptor Agonists ◽  
Μ Receptor

<b>Chronic pain is a major problem worldwide, affecting 1 in 5 New Zealanders resulting in a decreased quality of life for the patient and a large socioeconomic problem costing an estimated $13-$14.5 billion a year. Current therapeutics target the mu opioid receptor (μ receptor) and include drugs such as morphine and fentanyl. While these drugs are highly effective in the treatment of strong acute pain, their long-term use is associated with tolerance to the analgesic effects and increasing rates of side effects such as respiratory depression and constipation. Due to their high abuse liability, they are also known to cause dependence and addiction when prescribed for extended periods. This is believed to have played a role in the opioid crisis in the United States and highlights the need for improved therapeutics for the treatment of chronic pain. </b><p><br></p><p>One mechanism that has been proposed to generate μ receptor agonists for the treatment of chronic pain with reduced analgesic tolerance and safer side effects is the development of G-protein biased agonists. Such agonists selectively activate the canonical G-protein signalling to a greater extent than the non-canonical β-arrestin2 pathway. This is based on previous work in β-arrestin2 knockout mice where the antinociceptive effects were increased, while side effects, including respiratory depression, tolerance, and constipation are reduced, increasing the therapeutic window. In this thesis, we aimed to assess the anti-nociceptive and side effect behavioural profiles of two novel μ receptor agonists, kurkinol (bias = 0.14) and kurkinorin (bias = 0.57), with a varying bias for the G-protein pathway to assess the role of this paradigm. </p><p><br></p> Evaluation of the behavioural profile of kurkinol and kurkinorin revealed that G-protein bias was correlated to increased anti-nociceptive potency and reduced tolerance in wildtype C57BL/6J mice. Furthermore, the anti-nociceptive potency of morphine was increased, and tolerance decreased in in β-arrestin2 knockout mice. While the level of tolerance was reduced for kurkinorin. However, in the chemotherapy-induced model of neuropathic pain, tolerance to kurkinol and kurkinorin developed at the same rate as morphine. Overall this work showed a poor correlation between G-protein bias and therapeutic window. With the G-protein selective kurkinol inducing worse respiratory depression, constipation, and motor coordination impairment compared to kurkinorin. Interestingly, respiratory depressive and constipation effects of kurkinol were not prevented in the β-arrestin2 knockout mice indicating that they are induced through the G-protein pathway. <p><br></p><p>These results highlight the change that has occurred in the biased agonism field over the last 4 years, with the lack of reproducibility of key experiments and poor translation of G-protein biased μ receptor agonists resulting in improved therapeutic windows both clinically and pre-clinically. Moreover, recent research has shown that pathway efficacy (i.e. partial agonism) and not G-protein bias is responsible for the behavioural profiles of compounds previously identified as G-protein biased. We, therefore, decided to further investigate the cell signalling profiles of our two novel agonists to assess them for partial agonism and to assess downstream signalling molecules activated by G-protein and β-arrestin2. </p><div><br></div> This revealed cell-specific inhibition of membrane hyperpolarisation in Hek293 and CHO cells stably expressing the human μ receptor, with kurkinol found to be the most potent in both cell lines, followed by kurkinorin, morphine, and [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). However, no differences were identified between the μ receptor agonists in the activation of the inwardly rectifying channels in the CHO cell line. The assessment of pCREB (phosphorylated cAMP response-element binding protein) as a β-arrestin2 dependent pathway revealed poor activation by kurkinorin while kurkinol was a potent activator. Bias factors generated from this data showed poor correlations to therapeutic windows. While the differences om CREB phosphorylation was shown to have a stronger correlation to therapeutic windows generated from the behavioural data. <p><br></p><p>Overall this thesis has identified kurkinorin as a μ receptor agonist that induces potent anti-nociception with reduced side effects, without strong-G-protein bias. We also show that the highly selective μ receptor agonist kurkinol has improved anti-nociception with a worse side effect profile adding to the growing body of literature showing bias is not a good predictor in its current state. Furthermore, the discrepancies between cell lines, differential activation of subcellular pathways, and lack of reproducibility between bias equations indicate that the field has massively oversimplified a complex system. Which has, most likely, resulted in the poor translation of in vitro bias factors to clinically available μ receptor agonists for chronic pain. </p>

scholarly journals Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics

2020 ◽  
Vol 20 (31) ◽  
pp. 2878-2888 ◽  
Author(s):  
Norikazu Kiguchi ◽  
Huiping Ding ◽  
Shiroh Kishioka ◽  
Mei-Chuan Ko
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Physical Dependence ◽  
Opioid Peptide ◽  
Receptor Activation ◽  
Abuse Liability ◽  
Similar Distribution ◽  
Nop Receptor ◽  
Orphanin Fq ◽  
Receptor Agonists

Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and nonpeptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor- related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.

Differential effects of acetylsalicylic acid and acetaminophen on sleep abnormalities in a rat chronic pain model

1989 ◽  
Vol 488 (1-2) ◽  
pp. 195-201 ◽  
Author(s):  
Carol A. Landis ◽  
Connie R. Robinson ◽  
Clyde Helms ◽  
Jon D. Levine
Keyword(s):  
Chronic Pain ◽  
Acetylsalicylic Acid ◽  
Pain Model ◽  
Differential Effects ◽  
Sleep Abnormalities

scholarly journals Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

2021 ◽  
Author(s):  
Amy Alder
Keyword(s):  
Chronic Pain ◽  
Side Effects ◽  
G Protein ◽  
Respiratory Depression ◽  
Knockout Mice ◽  
Side Effect ◽  
Therapeutic Window ◽  
Receptor Agonists ◽  
Μ Receptor

<b>Chronic pain is a major problem worldwide, affecting 1 in 5 New Zealanders resulting in a decreased quality of life for the patient and a large socioeconomic problem costing an estimated $13-$14.5 billion a year. Current therapeutics target the mu opioid receptor (μ receptor) and include drugs such as morphine and fentanyl. While these drugs are highly effective in the treatment of strong acute pain, their long-term use is associated with tolerance to the analgesic effects and increasing rates of side effects such as respiratory depression and constipation. Due to their high abuse liability, they are also known to cause dependence and addiction when prescribed for extended periods. This is believed to have played a role in the opioid crisis in the United States and highlights the need for improved therapeutics for the treatment of chronic pain. </b><p><br></p><p>One mechanism that has been proposed to generate μ receptor agonists for the treatment of chronic pain with reduced analgesic tolerance and safer side effects is the development of G-protein biased agonists. Such agonists selectively activate the canonical G-protein signalling to a greater extent than the non-canonical β-arrestin2 pathway. This is based on previous work in β-arrestin2 knockout mice where the antinociceptive effects were increased, while side effects, including respiratory depression, tolerance, and constipation are reduced, increasing the therapeutic window. In this thesis, we aimed to assess the anti-nociceptive and side effect behavioural profiles of two novel μ receptor agonists, kurkinol (bias = 0.14) and kurkinorin (bias = 0.57), with a varying bias for the G-protein pathway to assess the role of this paradigm. </p><p><br></p> Evaluation of the behavioural profile of kurkinol and kurkinorin revealed that G-protein bias was correlated to increased anti-nociceptive potency and reduced tolerance in wildtype C57BL/6J mice. Furthermore, the anti-nociceptive potency of morphine was increased, and tolerance decreased in in β-arrestin2 knockout mice. While the level of tolerance was reduced for kurkinorin. However, in the chemotherapy-induced model of neuropathic pain, tolerance to kurkinol and kurkinorin developed at the same rate as morphine. Overall this work showed a poor correlation between G-protein bias and therapeutic window. With the G-protein selective kurkinol inducing worse respiratory depression, constipation, and motor coordination impairment compared to kurkinorin. Interestingly, respiratory depressive and constipation effects of kurkinol were not prevented in the β-arrestin2 knockout mice indicating that they are induced through the G-protein pathway. <p><br></p><p>These results highlight the change that has occurred in the biased agonism field over the last 4 years, with the lack of reproducibility of key experiments and poor translation of G-protein biased μ receptor agonists resulting in improved therapeutic windows both clinically and pre-clinically. Moreover, recent research has shown that pathway efficacy (i.e. partial agonism) and not G-protein bias is responsible for the behavioural profiles of compounds previously identified as G-protein biased. We, therefore, decided to further investigate the cell signalling profiles of our two novel agonists to assess them for partial agonism and to assess downstream signalling molecules activated by G-protein and β-arrestin2. </p><div><br></div> This revealed cell-specific inhibition of membrane hyperpolarisation in Hek293 and CHO cells stably expressing the human μ receptor, with kurkinol found to be the most potent in both cell lines, followed by kurkinorin, morphine, and [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). However, no differences were identified between the μ receptor agonists in the activation of the inwardly rectifying channels in the CHO cell line. The assessment of pCREB (phosphorylated cAMP response-element binding protein) as a β-arrestin2 dependent pathway revealed poor activation by kurkinorin while kurkinol was a potent activator. Bias factors generated from this data showed poor correlations to therapeutic windows. While the differences om CREB phosphorylation was shown to have a stronger correlation to therapeutic windows generated from the behavioural data. <p><br></p><p>Overall this thesis has identified kurkinorin as a μ receptor agonist that induces potent anti-nociception with reduced side effects, without strong-G-protein bias. We also show that the highly selective μ receptor agonist kurkinol has improved anti-nociception with a worse side effect profile adding to the growing body of literature showing bias is not a good predictor in its current state. Furthermore, the discrepancies between cell lines, differential activation of subcellular pathways, and lack of reproducibility between bias equations indicate that the field has massively oversimplified a complex system. Which has, most likely, resulted in the poor translation of in vitro bias factors to clinically available μ receptor agonists for chronic pain. </p>

scholarly journals Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

2021 ◽  
Author(s):  
Amy Alder
Keyword(s):  
Chronic Pain ◽  
Side Effects ◽  
G Protein ◽  
Respiratory Depression ◽  
Knockout Mice ◽  
Side Effect ◽  
Therapeutic Window ◽  
Receptor Agonists ◽  
Μ Receptor

<b>Chronic pain is a major problem worldwide, affecting 1 in 5 New Zealanders resulting in a decreased quality of life for the patient and a large socioeconomic problem costing an estimated $13-$14.5 billion a year. Current therapeutics target the mu opioid receptor (μ receptor) and include drugs such as morphine and fentanyl. While these drugs are highly effective in the treatment of strong acute pain, their long-term use is associated with tolerance to the analgesic effects and increasing rates of side effects such as respiratory depression and constipation. Due to their high abuse liability, they are also known to cause dependence and addiction when prescribed for extended periods. This is believed to have played a role in the opioid crisis in the United States and highlights the need for improved therapeutics for the treatment of chronic pain. </b><p><br></p><p>One mechanism that has been proposed to generate μ receptor agonists for the treatment of chronic pain with reduced analgesic tolerance and safer side effects is the development of G-protein biased agonists. Such agonists selectively activate the canonical G-protein signalling to a greater extent than the non-canonical β-arrestin2 pathway. This is based on previous work in β-arrestin2 knockout mice where the antinociceptive effects were increased, while side effects, including respiratory depression, tolerance, and constipation are reduced, increasing the therapeutic window. In this thesis, we aimed to assess the anti-nociceptive and side effect behavioural profiles of two novel μ receptor agonists, kurkinol (bias = 0.14) and kurkinorin (bias = 0.57), with a varying bias for the G-protein pathway to assess the role of this paradigm. </p><p><br></p> Evaluation of the behavioural profile of kurkinol and kurkinorin revealed that G-protein bias was correlated to increased anti-nociceptive potency and reduced tolerance in wildtype C57BL/6J mice. Furthermore, the anti-nociceptive potency of morphine was increased, and tolerance decreased in in β-arrestin2 knockout mice. While the level of tolerance was reduced for kurkinorin. However, in the chemotherapy-induced model of neuropathic pain, tolerance to kurkinol and kurkinorin developed at the same rate as morphine. Overall this work showed a poor correlation between G-protein bias and therapeutic window. With the G-protein selective kurkinol inducing worse respiratory depression, constipation, and motor coordination impairment compared to kurkinorin. Interestingly, respiratory depressive and constipation effects of kurkinol were not prevented in the β-arrestin2 knockout mice indicating that they are induced through the G-protein pathway. <p><br></p><p>These results highlight the change that has occurred in the biased agonism field over the last 4 years, with the lack of reproducibility of key experiments and poor translation of G-protein biased μ receptor agonists resulting in improved therapeutic windows both clinically and pre-clinically. Moreover, recent research has shown that pathway efficacy (i.e. partial agonism) and not G-protein bias is responsible for the behavioural profiles of compounds previously identified as G-protein biased. We, therefore, decided to further investigate the cell signalling profiles of our two novel agonists to assess them for partial agonism and to assess downstream signalling molecules activated by G-protein and β-arrestin2. </p><div><br></div> This revealed cell-specific inhibition of membrane hyperpolarisation in Hek293 and CHO cells stably expressing the human μ receptor, with kurkinol found to be the most potent in both cell lines, followed by kurkinorin, morphine, and [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). However, no differences were identified between the μ receptor agonists in the activation of the inwardly rectifying channels in the CHO cell line. The assessment of pCREB (phosphorylated cAMP response-element binding protein) as a β-arrestin2 dependent pathway revealed poor activation by kurkinorin while kurkinol was a potent activator. Bias factors generated from this data showed poor correlations to therapeutic windows. While the differences om CREB phosphorylation was shown to have a stronger correlation to therapeutic windows generated from the behavioural data. <p><br></p><p>Overall this thesis has identified kurkinorin as a μ receptor agonist that induces potent anti-nociception with reduced side effects, without strong-G-protein bias. We also show that the highly selective μ receptor agonist kurkinol has improved anti-nociception with a worse side effect profile adding to the growing body of literature showing bias is not a good predictor in its current state. Furthermore, the discrepancies between cell lines, differential activation of subcellular pathways, and lack of reproducibility between bias equations indicate that the field has massively oversimplified a complex system. Which has, most likely, resulted in the poor translation of in vitro bias factors to clinically available μ receptor agonists for chronic pain. </p>

Involvement of the Nociceptin/Orphanin FQ-NOP receptor system in the ventrolateral periaqueductal gray following mechanical allodynia in chronic pain

Life Sciences ◽  
2009 ◽  
Vol 85 (5-6) ◽  
pp. 206-210 ◽  
Author(s):  
Giovanna M. Scoto ◽  
Giuseppina Aricò ◽  
Attilio Iemolo ◽  
Simone Ronsisvalle ◽  
Carmela Parenti
Keyword(s):  
Chronic Pain ◽  
Mechanical Allodynia ◽  
Periaqueductal Gray ◽  
Nop Receptor ◽  
Orphanin Fq ◽  
Receptor System
Sign in / Sign up

Export Citation Format

Share Document