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

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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.

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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.

Ethical Statement

The authors declare that the experiments comply with the current laws of the United States of America.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston–Salem, NC, 27157, USA

    Devki D. Sukhtankar & Mei-Chuan Ko

  2. Department of Anesthesiology and Pain Medicine, School of Medicine, Ewha Womans University, Seoul, 158-710, South Korea

    Heeseung Lee

  3. Chemical Biology Research Branch, National Institute on Drug Abuse, Bethesda, MD, 20892, USA

    Kenner C. Rice

  4. Center for Comparative Medicine Research, Wake Forest University School of Medicine, Winston–Salem, NC, 27157, USA

    Mei-Chuan Ko

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  1. Devki D. Sukhtankar
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Correspondence to Devki D. Sukhtankar or Heeseung Lee.

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Sukhtankar, D.D., Lee, H., Rice, K.C. et al. Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain. Psychopharmacology 231, 1377–1387 (2014). https://doi.org/10.1007/s00213-013-3341-0

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  • DOI: https://doi.org/10.1007/s00213-013-3341-0

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