Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus

Jenny Morgenweck, Kevin J. Frankowski, Thomas E. Prisinzano, Jeffrey Aubé, Laura M. Bohn

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The kappa opioid receptor (KOR) is involved in mediating pruritus; agonists targeting this receptor have been used to treat chronic intractable itch. Conversely, antagonists induce an itch response at the site of injection. As a G protein-coupled receptor (GPCR), the KOR has potential for signaling via G proteins and βarrestins, however, it is not clear which of these pathways are involved in the KOR modulation of itch. In this study asked whether the actions of KOR in pruritus involve βarrestins by using βarrestin2 knockout (βarr2-KO) mice as well as a recently described biased KOR agonist that biases receptor signaling toward G protein pathways over βarrestin2 recruitment. We find that the KOR antagonists nor-binaltorphimine (NorBNI) and 5′-guanidinonaltrindole (5′GNTI) induce acute pruritus in C57BL/6J mice, with reduced effects in KOR-KO mice. βArr2-KO mice display less of a response to KOR antagonist-induced itch compared to wild types, however no genotype differences are observed from chloroquine phosphate (CP)-induced itch, suggesting that the antagonists may utilize a KOR-βarrestin2 dependent mechanism. The KOR agonist U50,488H was equally effective in both WT and βarr2-KO mice in suppressing CP-induced itch. Furthermore, the G protein biased agonist, Isoquinolinone 2.1 was as effective as U50,488H in suppressing the itch response induced by KOR antagonist NorBNI or CP in C57BL/6J mice. Together these data suggest that the antipruritic effects of KOR agonists may not require βarrestins.

Original languageEnglish
Pages (from-to)600-609
Number of pages10
JournalNeuropharmacology
Volume99
DOIs
StatePublished - Dec 9 2015

Bibliographical note

Funding Information:
We thank Stephen Slauson of KU for his chemical synthesis efforts. This work was funded by NIDA grant R01DA031927 to L. Bohn and J. Aubé.

Publisher Copyright:
© 2015 Elsevier Ltd.All rights reserved.

Keywords

  • Biased ligand
  • KOR antagonist
  • Kappa opioid receptor
  • Mouse models of itch
  • Pruritus
  • U50,488H

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus'. Together they form a unique fingerprint.

Cite this