Nalfurafine suppresses pruritogen- and touch-evoked scratching behavior in models of acute and chronic itch in mice

Abstract

The kappa-opioid agonist, nalfurafine, has been approved in Japan for treatment of itch in patients with chronic kidney disease. We presently investigated if systemic administration of nalfurafine inhibited ongoing or touch-evoked scratching behavior (alloknesis) following acute intradermal injection of histamine or the non-histaminergic itch mediator, chloroquine, in mice. We also investigated if nalfurafine suppressed spontaneous or touch-evoked scratching in an experimental model of chronic dry skin itch. Nalfurafine reduced scratching evoked by histamine and chloroquine. Following acute histamine, but not chloroquine, low-threshold mechanical stimuli reliably elicited directed hindlimb scratching behavior, which was significantly attenuated by nalfurafine. In mice with experimental dry skin, nalfurafine abolished spontaneous scratching but had no effect on alloknesis. Nalfurafine thus appears to be a promising treatment for acute itch as well as ongoing itch of dry skin.

Fig. 1

Nalfurafine inhibits scratching and alloknesis elicited by intradermal (i.d.) histamine and chloroquine. A: Bar graph shows the mean number of scratch bouts/30 min after i.d. injection of histamine (His-Sal) or chloroquine (CQ-Sal) in animals pretreated with saline. Additional groups received i.d. histamine following pretreatment with nalfurafine (His-Nalf, 10 or 20 μg/kg), or i.d .chloroquine following pretreatment with nalfurafine (CQ-Nalf 20 μg/kg). Error bars are SEM (n = 6/group). *p < 0.05, significantly different from saline-treated group (one way ANOVA followed by Bonferroni test or unpaired t-test). B: As in A for the alloknesis scores averaged over 30 min (i.e., maximum score is 21). Error bars are SEM (n=6/group). *p < 0.05, significantly difffence from saline-treated group (one way ANOVA followed by Bonferroni test).

Fig. 2

κ-opioid agonist nalfurafine inhibits spontaneous scratching, but not alloknesis in dry skin-treated mice. A: Dry skin was induced by twice-daily treatment with acetone ether water (AEW) over 8 days. Bar graph shows the mean number of scratch bouts/60 min following pretreatment with saline (black bar) or nalfurafine (gray bar) at day 0 (i.e, prior to AEW treatment) and at AEW treatment day 8. Error bars are SEM (n = 5–6/group). *p < 0.05, significantly different compared to saline-treated group on day 0 (paired t-test). Nalfurafine completely inhibited spontaneous scratching. B: As in A for the alloknesis score. Error bars are SEM (n = 5–6/group). Nalfurafine had no significant effect on alloknesis.