Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

Devki D. Sukhtankar; Heeseung Lee; Kenner C. Rice; Mei Chuan Ko

doi:10.1007/s00213-013-3341-0

Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

Devki D. Sukhtankar, Heeseung Lee, Kenner C. Rice, Mei Chuan Ko

Department of Anesthesia and Pain Medicine

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

Rationale: Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates. Objective: The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs). Results: Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception. Conclusion: Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.

Original language	English
Pages (from-to)	1377-1387
Number of pages	11
Journal	Psychopharmacology
Volume	231
Issue number	7
DOIs	https://doi.org/10.1007/s00213-013-3341-0
State	Published - Apr 2014

Bibliographical note

Funding Information:
Acknowledgments We thank Tristan Edwards and John Busenbark for technical assistance of data collection. Research reported in this publication was supported by the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases under Award number R01-AR-059193, and the National Institute on Drug Abuse under Award number R01-DA-032568. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

Carrageenan
Hyperalgesia
Monkey pain model
NOP receptors
NSAIDs
Nociceptin/orphanin FQ
Opioid receptors
Opioids

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title = "Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain",

abstract = "Rationale: Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates. Objective: The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs). Results: Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception. Conclusion: Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.",

keywords = "Carrageenan, Hyperalgesia, Monkey pain model, NOP receptors, NSAIDs, Nociceptin/orphanin FQ, Opioid receptors, Opioids",

author = "Sukhtankar, {Devki D.} and Heeseung Lee and Rice, {Kenner C.} and Ko, {Mei Chuan}",

note = "Funding Information: Acknowledgments We thank Tristan Edwards and John Busenbark for technical assistance of data collection. Research reported in this publication was supported by the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases under Award number R01-AR-059193, and the National Institute on Drug Abuse under Award number R01-DA-032568. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.",

year = "2014",

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doi = "10.1007/s00213-013-3341-0",

language = "English",

volume = "231",

pages = "1377--1387",

journal = "Psychopharmacology",

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T1 - Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

AU - Sukhtankar, Devki D.

AU - Lee, Heeseung

AU - Rice, Kenner C.

AU - Ko, Mei Chuan

N1 - Funding Information: Acknowledgments We thank Tristan Edwards and John Busenbark for technical assistance of data collection. Research reported in this publication was supported by the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases under Award number R01-AR-059193, and the National Institute on Drug Abuse under Award number R01-DA-032568. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

PY - 2014/4

Y1 - 2014/4

N2 - Rationale: Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates. Objective: The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs). Results: Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception. Conclusion: Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.

AB - Rationale: Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates. Objective: The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs). Results: Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception. Conclusion: Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.

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KW - Nociceptin/orphanin FQ

KW - Opioid receptors

KW - Opioids

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Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

Abstract

Bibliographical note

Keywords

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