Promising New Compound Could Treat Chronic Itch Without Adverse Side Effects

If you have an itch, you have to scratch it. But that’s a problem for people with a condition called “chronic intractable itch,” where that itchy sensation never goes away–a difficult-to-treat condition closely associated with dialysis and renal failure.

In a new study, scientists from the Florida campus of The Scripps Research Institute (TSRI) describe a class of compounds with the potential to stop chronic itch without the adverse side effects normally associated with medicating the condition.

“Our lab has been working on compounds that preserve the good properties of opioids and eliminate many of the side effects,” said TSRI Professor Laura Bohn. “The new paper describes how we have refined an aspect of signaling underlying how the drugs work at the receptor so they still suppress itch and do not induce sedation. Developing compounds that activate the receptors in this way may serve as a means to improve their therapeutic potential.”

The study, which was published recently in the journal Neuropharmacology, used a compound called isoquinolinone 2.1 to target the kappa opioid receptor, which is widely expressed in the central nervous system and serves to moderate pain perception and stress responses.

The compound was effective in stopping irritant-induced itch, without causing sedation, in mouse models of the condition.

Image shows a person scratching their arm.
The compound was effective in stopping irritant-induced itch, without causing sedation, in mouse models of the condition. Credit: Orrling and Tomer S.

Bohn noted isoquinolinone 2.1 is one example of a new class of “biased” kappa agonists that avoid many central nervous system side effects by preferentially activating a G protein-mediated signaling cascade without involving another system based on β-arrestin protein interactions.

About this neuropharmacology research

The first author of the study, “Investigation of the Role of Beta Arrestin2 in Kappa Opioid Receptor Modulation in a Mouse Model of Pruritus,” was Jenny Morgenweck. Other authors include Kevin J. Frankowski, Thomas E. Prisinzano and Jeffrey Aubé of The University of Kansas and the University of North Carolina-Chapel Hill.

Funding: The work was supported by the National Institutes of Health’s National Institute on Drug Abuse (grant R01DA031927).

Source: Scripps Research Institute
Image Source: The image is credited to Orrling and Tomer S and is licensed CC BY-SA 3.0
Original Research: Abstract for “Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus” by Jenny Morgenweck, Kevin J. Frankowski, Thomas E. Prisinzano, Jeffrey Aubé, and Laura M. Bohn in Neuropharmacology. Published online August 25 2015 doi:10.1016/j.neuropharm.2015.08.027


Abstract

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

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.

“Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus” by Jenny Morgenweck, Kevin J. Frankowski, Thomas E. Prisinzano, Jeffrey Aubé, and Laura M. Bohn in Neuropharmacology. Published online August 25 2015 doi:10.1016/j.neuropharm.2015.08.027

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