Behavioral Effects of a Synthetic Agonist Selective for Nociceptin/Orphanin FQ Peptide Receptors in Monkeys

Ko, Mei‐Chuan; Woods, James H.; Fantegrossi, William E.; Galuska, Chad M.; Wichmann, Jürgen; Prinssen, Eric

doi:10.1038/npp.2009.33

Cited by 88 publications

(99 citation statements)

References 41 publications

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“…82 Contrary to the results from rodent studies, systemic administration of Ro 64−6198 produced antinociceptive effects against acute noxious stimulus in monkeys. 83,84 Importantly, systemic Ro 64−6198 produced antiallodynic effects in the primate capsaicin-induced allodynia model. Capsaicin elicits pain sensation by activating the vanilloid receptor and stimulating the release of pronociceptive neuropeptides.…”

Section: ■ Effects Of Systemic Nop-related Ligandsmentioning

confidence: 99%

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

Lin

2012

ACS Chem. Neurosci.

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Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/ orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans.

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Section: ■ Effects Of Systemic Nop-related Ligandsmentioning

confidence: 99%

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

Lin

2012

ACS Chem. Neurosci.

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“…A single dose of MOP receptor-selective antagonist naltrexone (0.03 mg/kg) or NOP receptor-selective antagonist J-113397 (0.1 mg/kg) was administered s.c. at 15 min before determination of doseresponse curves to compare their antagonist effects against BU08028-induced antinociception. The doses and pretreatment time for both naltrexone and J-113397 were chosen based on previous studies (23,25). Capsaicin-induced thermal allodynia.…”

Section: Methodsmentioning

confidence: 99%

“…We next conducted antagonist studies using a MOP receptorselective dose of the opioid receptor antagonist naltrexone and the selective NOP receptor antagonist J-113397 (21,23). Pretreatment with a single dose of naltrexone (0.03 mg/kg) or J-113397 (0.1 mg/kg) produced similar degrees (dose ratios approximately threefold) of the rightward shift of the dose-response curve for BU08028-induced antinociception (Fig.…”

Section: Bu08028 Produces Potent and Long-lasting Antinociceptive Andmentioning

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). More importantly, NOP agonists interact with buprenorphine in a synergistic manner to produce antinociceptive effects (25).…”

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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.

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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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“…However, no firm conclusion can be made on the long-term effect and the clinical usefullness of alfentanil (Ko et al, 2009;Offenbaecher and Ackenheil, 2005).…”

Section: Drug Classification (Offenbaecher Andmentioning

confidence: 99%

Pharmacotherapy of Neuropathic Pain

Otari¹,

Shete²,

Upasani³

2012

Neuropathic Pain

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Behavioral Effects of a Synthetic Agonist Selective for Nociceptin/Orphanin FQ Peptide Receptors in Monkeys

Cited by 88 publications

References 41 publications

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

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

Pharmacotherapy of Neuropathic Pain

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