The Role of Central μ Opioid Receptors in Opioid-Induced Itch in Primates

Ko, Mei‐Chuan; Song, Michael S.; Edwards, Taylor; Lee, H.; Naughton, Norah N.

doi:10.1124/jpet.103.061101

Cited by 134 publications

(148 citation statements)

References 37 publications

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“…The monkeys' behaviors were recorded in their home cages for scratching activity, which has been associated previously with itch sensation (48). Each 15-min recording session was conducted at multiple time points after s.c. administration of BU08028 or fentanyl.…”

Section: Methodsmentioning

confidence: 99%

“…To examine whether BU08028 elicits itch sensation, we compared its effects with the MOP receptor agonist fentanyl, which was previously shown to elicit scratching responses in monkeys (48). Although BU08028 0.01 mg/kg produced potent and long-lasting antinociceptive and antihypersensitive effects, it did not significantly increase scratching responses [F(1, 3) = 4.5; P = 0.1].…”

Section: Bu08028 Produces Potent and Long-lasting Antinociceptive Andmentioning

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: Methodsmentioning

confidence: 99%

Section: Bu08028 Produces Potent and Long-lasting Antinociceptive Andmentioning

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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“…[45] The pharmacological studies in non-human primates also found that an antihistamine such as diphenhydramine, in a wide range of doses could not attenuate the intrathecal morphineinduced pruritus [22]. In addition, other agonists of MOP as fentanyl and alfentanil do not stimulate the release of histamine, while they evoke pruritus/scratching in humans and non-human primates [46].…”

Section: Other Drugs Nsaidsmentioning

confidence: 99%

“…The pre-treatment with clocinamox, a selective antagonist receptor, inhibited scratching induced by spinal opioids in primates, but neither the antagonism κ-opioid (binaltorfimina) nor the antagonists delta (naltrindol) produce this effect. This would explain the fundamental antipruritic role of the antagonists to mu receptors [22]. Accordingly, many studies have evaluated the efficacy of naloxone, naltrexone and methylnaltrexone in the prevention of pruritus, but results were observed variables.…”

Section: Prevention and Treatment Of Neuraxial Opioid Induced Pruritusmentioning

confidence: 99%

An Update on Neuraxial Opioid Induced Pruritus Prevention

2016

JACCOA

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“…Clocinamox, a selective MOR antagonist pre-treatment in an animal model, inhibited scratching induced by spinal opioids in primates, but the KOR antagonist binaltorfimina or the delta opioid receptor (DOR) antagonist naltrindol did not produce this clinical effect. This fact would explain the great antipruritic role of MOR antagonists [11]. Accordingly, some studies have evaluated the efficacy of naloxone, naltrexone and methylnaltrexone in the prevention of pruritus, but results observed were variable.…”

Section: Opioid Receptor Antagonistsmentioning

confidence: 99%