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The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys

Abstract

Rationale

The synthetic nonpeptide NOP (nociceptin/orphanin FQ peptide) receptor agonist Ro 64-6198 produces antinociception in rhesus monkeys. In rodents, it has much more variable effects on pain responses, but has response rate-increasing effects on punished operant behavior and decreases drug reward.

Objectives

The aim of this study was to compare Ro 64-6198 with the benzodiazepine diazepam in tests of analgesia, drug self-administration, and response-increasing effects in rhesus monkeys.

Results

Ro 64-6198 (0.001–0.01 mg/kg, i.v.) produced antinociception against an acute noxious stimulus (50°C water) in the absence of sedation, whereas diazepam (0.32–3.2 mg/kg, i.v.) did not have analgesic effects without sedation. Diazepam (1.0–5.6 mg/kg, i.v.) and the largest dose of Ro 64-6198 (0.32 mg/kg, i.v.) decreased lever pressing maintained by intravenous self-administration of the mu-opioid agonist, remifentanil, but neither effect could be distinguished from sedative effects. Although neither drug consistently increased responding during nonreinforcement, such effects were observed more frequently following diazepam administration. The effects of Ro 64-6198 on lever pressing were blocked by the NOP-receptor antagonist, J-113397, but not by the benzodiazepine antagonist, flumazenil.

Conclusions

These findings suggest that the effects of Ro 64-6198 on operant lever pressing are mediated by NOP receptors and that larger doses are required to impact operant behavior when compared directly with those that produce antinociception. Therefore, the present findings support previous literature suggesting NOP receptors are a viable target for pain management.

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Acknowledgments

We thank Eric Hu and Kelly Tuzi for technical assistance of data collection in the nociception study and Kathy Carey, Amy Hall, and Susan Pouliot for technical assistance in the remifentanil self-administration study. We also thank Corina Jimenez-Gomez for helpful comments on a previous version of this manuscript. This study was supported by U.S. Department of Defense, Peer Reviewed Medical Research Program, Grant W81XWH-07-1-0162 to MCK and U.S. Public Health Service Grants DA-015449 and DA-023992 to GW. CAP was supported by the National Institutes of Health under Ruth L. Kirschstein National Service Research Service Award T32 DA007268. The authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service except as listed below, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. The author MCK received research support from Grunenthal GmbH, Ingenium Pharmaceuticals, Elan Pharmaceuticals, and Purdue Pharma. The author JHW received research support from Grunenthal GmbH, Alkermes, Roche, Adolor Corporation, and Reckitt Benckiser Pharmaceuticals.

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Correspondence to Christopher A. Podlesnik.

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Podlesnik, C.A., Ko, MC., Winger, G. et al. The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys. Psychopharmacology 213, 53–60 (2011). https://doi.org/10.1007/s00213-010-2012-7

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  • DOI: https://doi.org/10.1007/s00213-010-2012-7

Keywords

  • Antinociception
  • Self-administration
  • NOP receptor
  • Ro 64-6198
  • J-113397
  • Benzodiazepine
  • Diazepam
  • Flumazenil
  • Remifentanil
  • Rhesus monkey