title: Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus.
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.
authors: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA; Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA.
authors: Jenny
authors: J
authors: Morgenweck
authors: Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
authors: Kevin J
authors: KJ
authors: Frankowski
authors: Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
authors: Thomas E
authors: TE
authors: Prisinzano
authors: Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
authors: Jeffrey
authors: J
authors: Aubé
authors: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA; Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, #2A2, Jupiter, FL 33458, USA. Electronic address: lbohn@scripps.edu.
authors: Laura M
authors: LM
authors: Bohn
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002738:Chloroquine / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006146:Guanidines; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009019:Morphinans; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009271:Naltrexone / Q000031:analogs & derivatives; D011537:Pruritus / Q000188:drug therapy* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; D000701:Analgesics, Opioid; D019390:Arrestins; D006146:Guanidines; D007546:Isoquinolines; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D000071557:beta-Arrestins; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C023676:chloroquine diphosphate; D002738:Chloroquine
keywords: Biased ligand; KOR antagonist; Kappa opioid receptor; Mouse models of itch; Pruritus; U50,488H