Effects of Spinally Administered Bifunctional Nociceptin/Orphanin FQ Peptide Receptor/<i>μ</i>-Opioid Receptor Ligands in Mouse Models of Neuropathic and Inflammatory Pain

Sukhtankar, Devki; Zaveri, Nurulain T.; Husbands, Stephen M.; Ko, Mei‐Chuan

doi:10.1124/jpet.113.203984

Cited by 54 publications

(45 citation statements)

References 46 publications

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“…Nonetheless, repeated intrathecal or i.p. administration of drugs with dual MOP/NOP receptor agonist activity (e.g., SR16435, cebranopadol) was found to result in slower development of tolerance to their antiallodynic effects compared with MOP agonists in rodents under neuropathic pain (35,36). Morphine and buprenorphine have different analgesic potencies and tolerance development in humans, with a faster onset of tolerance to morphine (6,59).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…Subsequent to chemical modifications, some of these ligands exhibited antinociceptive and antihypersensitive efficacy with improved potency across different rodent pain models (31,(34)(35)(36). However, in vivo functional profiles of these ligands in primates are completely unknown.…”

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.

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102

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“…Tactile allodynia was measured in mice with chronic constriction injury as paw withdrawal thresholds in response to probing the ipsilateral paw with calibrated von Frey filaments as described previously (Sukhtankar et al, 2013). No changes were observed in withdrawal thresholds of the contralateral paw.…”

Section: Mouse Studiesmentioning

confidence: 99%

“…in the volume of 5 μL as previously described (Sukhtankar et al, 2013). Briefly, the mouse was secured by a firm grip on the pelvic girdle, and the test drug was delivered by lumbar puncture between the L5/L6 vertebrae using a 30 G needle attached to a 10 μL Hamilton syringe.…”

Section: Monkey Studiesmentioning

confidence: 99%

Spinal antinociceptive effects of the novel NOP receptor agonist PWT2‐nociceptin/orphanin FQ in mice and monkeys

Rizzi

Sukhtankar

Ding

et al. 2015

British J Pharmacology

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Background and purposeUsing an innovative chemical approach, peptide welding technology (PWT), a tetrabranched derivative of nociceptin/orphanin FQ (N/OFQ) has been generated and pharmacologically characterized. Both in vitro and in vivo PWT2‐N/OFQ displayed the same pharmacological profile to the natural ligand. It was more potent and produced longer‐lasting effects. The aim of the present study was to investigate the spinal effects of PWT2‐N/OFQ in nociceptive and neuropathic pain models in mice and non‐human primates.Experimental ApproachTail withdrawal assay in mice and monkeys was used as a nociceptive pain model and mechanical threshold in mice subjected to chronic constriction injury was used as a neuropathic pain model. The antinociceptive effects of spinally administered N/OFQ and PWT2‐N/OFQ were assessed in these models.Key ResultsPWT2‐N/OFQ mimicked the spinal antinociceptive effects of N/OFQ both in nociceptive and neuropathic pain models in mice as well as in non‐human primates displaying 40‐fold higher potency and a markedly prolonged duration of action. The effects of N/OFQ and PWT2‐N/OFQ were sensitive to the N/OFQ receptor (NOP) antagonist SB‐612111, but not to opioid receptor antagonists.Conclusions and ImplicationsThe present study has demonstrated that PWT2‐N/OFQ mimicked the antinociceptive effects of the natural peptide in rodents and non‐human primates acting as a potent and longer‐lasting NOP‐selective agonist. More generally, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.

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“…[9][10][11] Agonists and antagonists of NOP/R have been demonstrated to influence pain at the peripheral, spinal and supraspinal level in rodent models of neuropathic and inflammatory pain. [12][13][14] The anti-nociceptive role of spinal NOP/Rs is suggested to result from an inhibitory action on SP-mediated nociception via second-order neurons. 15 SP levels are increased in the serum of patients with SCA and in sickle mice compared to healthy subjects and control mice, respectively.…”

Section: Introductionmentioning

confidence: 99%

Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice

et al. 2015

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Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule nociceptin opioid receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity nociceptin opioid receptor agonist with low efficacy at the mu opioid receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice. The antinociceptive effect of AT-200 was antagonized by SB-612111, a nociceptin opioid receptor antagonist, but not naloxone, a nonselective mu opioid receptor antagonist. Daily 7-day treatment with AT-200 did not develop tolerance and showed a sustained anti-nociceptive effect, which improved over time and led to reduced plasma serum amyloid protein, neuropeptides, inflammatory cytokines and mast cell activation in the periphery. These data suggest that AT-200 ameliorates pain in sickle mice via the nociceptin opioid receptor by reducing inflammation and mast cell activation without causing tolerance. Thus, nociceptin opioid receptor agonists are promising drugs for treating pain in sickle cell anemia.

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Effects of Spinally Administered Bifunctional Nociceptin/Orphanin FQ Peptide Receptor/μ-Opioid Receptor Ligands in Mouse Models of Neuropathic and Inflammatory Pain

Cited by 54 publications

References 46 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

Spinal antinociceptive effects of the novel NOP receptor agonist PWT2‐nociceptin/orphanin FQ in mice and monkeys

Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice

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