Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Toll, Lawrence; Bruchas, Michael R.; Calò, Girolamo; Cox, Brian M.; Zaveri, Nurulain T.

doi:10.1124/pr.114.009209

Cited by 237 publications

(215 citation statements)

References 362 publications

(464 reference statements)

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“…Given that capsaicin-sensitive nerve fibers are involved in a variety of pain conditions, the full effectiveness of BU08028 in inhibiting capsaicin-induced allodynia may indicate its clinically relevant analgesic efficacy. In addition, rodent studies have demonstrated the analgesic efficacy of NOP-related agonists across diverse pain modalities, including inflammatory pain, neuropathic pain, and sickle cell pain (18,20,22,29). Cumulative evidence supports a broad application of NOP-related agonists as analgesics.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Ding

Czoty

Kiguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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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 wellhoned 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 abusefree opioid analgesics.N/OFQ peptide receptor | respiratory depression | reinforcing effects | physical dependence | mu opioid peptide receptor P ain, a symptom of numerous clinical disorders, afflicts millions of people worldwide. Despite the remarkable advances in the identification of potential targets as analgesics in the last decade, mu opioid peptide (MOP) receptor agonists remain the most widely used analgesics for pain management (1). Several side effects associated with MOP receptor agonists have severely limited the value of opioid analgesics, however (2). Owing to the abuse liability and the high mortality rate caused by respiratory arrest, opioid abuse not only has dire consequences, but also leads to mounting medical and economic burdens in our society (3-5). There is a clear, unmet need for safe analgesics without abuse liability in the global community.Buprenorphine, a partial MOP receptor agonist, is considered a safe analgesic because of its ceiling effect on respiratory depression (6, 7). Buprenorphine is commonly used in both human and veterinary medicine to treat various pain conditions, including cancer pain and neuropathic pain (7,8). However, buprenorphine is not devoid of reinforcing effects, the most devastating side effect...

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Section: Discussionmentioning

confidence: 99%

“…(17)(18)(19)(20). Following spinal and systemic administration, NOP receptor agonists produce antinociception and antihypersensitivity comparable to those of MOP receptor agonists, but without reinforcing effects in nonhuman primates (21)(22)(23)(24).…”

mentioning

confidence: 99%

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

Ding

Czoty

Kiguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Buprenorphine has no DOP agonist activity, but is a DOP antagonist [61]. The effects of the NOP receptor on stress-related behaviour are less well characterized [77]. NOP receptor agonists have been shown to have anxiolytic-like effects comparable with those of benzodiazepines in a range of behavioural assays [78].…”

Section: Future Prospects For Opioid Ligands In the Treatment Of Mood?mentioning

confidence: 99%

Targeting opioid receptor signaling in depression: do we need selective κ opioid receptor antagonists?

Bailey

Husbands

2018

Neuronal Signaling

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The opioid receptors are a family of G-protein coupled receptors (GPCRs) with close structural homology. The opioid receptors are activated by a variety of endogenous opioid neuropeptides, principally β-endorphin, dynorphins, leu-and met-enkephalins. The clinical potential of targeting opioid receptors has largely focused on the development of analgesics. However, more recent attention has turned to the role of central opioid receptors in the regulation of stress responses, anhedonia and mood. Activation of the κ opioid receptor (KOP) subtype has been shown in both human and rodent studies to produce dysphoric and pro-depressive like effects. This has led to the idea that selective KOP antagonists might have therapeutic potential as antidepressants. Here we review data showing that mixed μ opioid (MOP) and KOP antagonists have antidepressant-like effects in rodent behavioural paradigms and highlight comparable studies in treatment-resistant depressed patients. We propose that developing multifunctional ligands which target multiple opioid receptors open up the potential for fine-tuning hedonic responses mediated by opioids. This alternative approach towards targeting multiple opioid receptors may lead to more effective treatments for depression.

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“…This member of the opioid receptors is involved in the regulation of many midbrain activities, especially pain transmission, feeding, memory, learning, stress and anxiety. 45 The NOR acts as a dopamine endogenous antagonist that may act either by the blocking GABA or directly on dopamine to affect dopamine levels. NOR has been shown to have a hyperalgesic or anti-analgesic effect.…”

Section: Nociceptin Orphanin Fq Receptor (Nor)mentioning

confidence: 99%

The pathophysiological role of serotonin receptor systems in opioid analgesia and tolerance

Özdemir

2017

Int J Basic Clin Pharmacol

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Continuous treatment with opioid analgesics, such as morphine, leads to the development of ant nociceptive tolerance in patients. Although a lot of information about antinociceptive, the pathophysiological mechanisms of tolerance to opioid analgesia are not yet completely understood. Proposed mechanisms for opioid analgesic tolerance comprise down-regulation of opioid receptors, reduction of sensitivity G-proteins, altered intracellular signalling pathway including nitric oxide, adenyl cyclase, and protein kinase C. Numerous physiological and behavioural studies have shown an interaction of the serotonergic system and opioid antinociception. The serotonin (5-HT) receptor system is a necessary component of the spinal and midbrain pain modulation circuit mediating opioid analgesia. Various types of serotonin receptors demonstrate different effects on morphine analgesia. Systemic administration of opioids rise 5-HT levels in the spinal cord dorsal horn and contribute to opioid analgesia in the normal state but reduce that in neuropathic pain via spinal 5-HT3 receptors. Spinal and supraspinal serotonergic neurons may also play a pathophysiological role in the development of morphine analgesic tolerance. Serotonin receptor subtypes show different effects on opioid tolerance. This review paper focus on the current understanding of the role of serotonin receptor systems in opioid analgesia and tolerance.

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Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Cited by 237 publications

References 362 publications

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

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

Targeting opioid receptor signaling in depression: do we need selective κ opioid receptor antagonists?

The pathophysiological role of serotonin receptor systems in opioid analgesia and tolerance

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