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Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats

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Abstract

Rationale

Nalfurafine is a G protein signaling-biased kappa opioid receptor (KOR) agonist approved in Japan for second-line treatment of uremic pruritus. Neither nalfurafine nor any other KOR agonist is currently approved anywhere for treatment of pain, but recent evidence suggests that G protein signaling-biased KOR agonists may have promise as candidate analgesics/antipruritics with reduced side effects compared to nonbiased or ß-arrestin-signaling-biased KOR agonists.

Objectives

This study compared nalfurafine effects in rats using assays of pain-stimulated and pain-depressed behavior used previously to evaluate other candidate analgesics. Nalfurafine effects were also examined in complementary assays of itch-stimulated and itch-depressed behavior.

Methods

Intraperitoneal lactic acid (IP acid) and intradermal serotonin (ID 5HT) served as noxious and pruritic stimuli, respectively, in male Sprague Dawley rats to stimulate stretching (IP acid) or scratching (ID 5HT) or to depress positively reinforced operant responding in an assay of intracranial self-stimulation (ICSS; both stimuli).

Results

Nalfurafine was equipotent to decrease IP acid-stimulated stretching and ID 5HT-stimulated scratching; however, doses of nalfurafine that decreased these pain/itch-stimulated behaviors also decreased control ICSS performance. Moreover, nalfurafine failed to alleviate either IP acid- or ID 5HT-induced depression of ICSS.

Conclusions

These results suggest that nalfurafine-induced decreases in pain/itch-stimulated behaviors may reflect nonselective decreases in motivated behavior rather than analgesia or antipruritus against the noxious and pruritic stimuli used here. This conclusion agrees with the absence of clinical data for nalfurafine analgesia and the weak clinical data for nalfurafine antipruritus. Nalfurafine bias for G protein signaling may not be sufficient for clinically safe and reliable analgesia or antipruritus.

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Acknowledgements

This study was supported by NIH grants R01NS070715, R01DA039167, R01DA009045, and T32DA007027.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Matthew L. Lazenka, Megan J. Moerke & S. Stevens Negus

  2. Division of Neurobiology and Behavior Research, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA

    E. Andrew Townsend & Kevin B. Freeman

  3. Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC, USA

    F. Ivy Carroll

Authors
  1. Matthew L. Lazenka
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  2. Megan J. Moerke
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  3. E. Andrew Townsend
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  4. Kevin B. Freeman
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  5. F. Ivy Carroll
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  6. S. Stevens Negus
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Contributions

Dr. Lazenka contributed as a postdoctoral fellow from the Negus Lab at VCU. He conducted most of the studies, analyzed data, prepared figures, and worked with the senior author to write manuscript drafts and incorporate author comments into the final version of the manuscript.

Dr. Moerke also contributed as a postdoctoral fellow from the Negus Lab at VCU. She conducted studies, performed initial data analysis and interpretation on the studies she conducted, contributed comments to manuscript drafts, and approved the final version of the manuscript.

Drs. Townsend and Freeman consulted on issues of experimental design regarding the behavioral pharmacology of nalfurafine, contributed comments to manuscript drafts, and approved the final version of the manuscript.

Dr. Carroll provided JDTic, consulted on issues of experimental design regarding the behavioral pharmacology of JDTic, contributed comments to manuscript drafts, and approved the final version of the manuscript.

Dr. Negus supervised all aspects of experimental design, conduct, analysis, and interpretation and worked the first author to write manuscript drafts and incorporate author comments into the final version of the manuscript.

Corresponding author

Correspondence to S. Stevens Negus.

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Lazenka, M.L., Moerke, M.J., Townsend, E.A. et al. Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats. Psychopharmacology 235, 203–213 (2018). https://doi.org/10.1007/s00213-017-4758-7

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  • DOI: https://doi.org/10.1007/s00213-017-4758-7

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