Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse

Abstract

Itch features considerable interindividual variability in humans, and initial studies using animal models have demonstrated a likely role of genetic factors in mediating such variability. In an attempt to systematically study genetic mediation of itch in the mouse such that gene identification by linkage mapping might be achieved, we examined scratching behavior induced by histamine and chloroquine in mice of 11 inbred mouse strains. Multiple chloroquine drug doses were used, revealing the existence of inverted-U dose-response relationships in every strain, allowing us to determine strain-dependent peak scratching behavior over the entire dose range. Peak chloroquine-induced scratching varied by 2.5-fold in this set of strains; scratching behavior shows moderate heritability in the mouse. The present data also reveal, for the first time, significant sex differences in pruritogen-induced scratching behavior, with female mice scratching an average of 23% more than males. Finally, a comparison of the strain means obtained here with previously collected data using nociceptive assays revealed a suggestive negative genetic correlation between chloroquine-induced itch and thermal pain, such that strains sensitive to pain are resistant to itch and vice versa. This finding may have implications both for our understanding of itch pathophysiology and for the identification of itch-related genes.

Scratching Behavior and Fos Expression in Superficial Dorsal Horn Elicited by Protease-Activated Receptor Agonists and Other Itch Mediators in Mice

“…Histamine elicited dose-dependent scratching ( Fig. 1), confirming previous studies showing robust scratching in ICR mice with variable efficacy in other strains (Inagaki et al, 2001;Green et al, 2006;Shimada and LaMotte, 2008) that is mediated via H1 and H4 histamine receptors (Ohtsuka et al, 2001;Bell et al, 2004). Histamine-evoked scratching exhibited significant tachyphylaxis, consistent with reduced itch sensation upon repeated challenge with histamine in humans (Ståhle-Bä ckdahl et al, 1988).…”

“…In contrast, intradermal histamine induces a local flare and itch sensation by exciting a different population of mechanically insensitive C-fiber afferents (Schmelz et al, 1997), as well as mechanosensitive C-fiber nociceptors to varying degrees (Handwerker et al, 1991;Johanek et al, 2008). Histamine also elicits dose-related scratching behavior in ICR mice and variable (or no) scratching in other mouse strains (Kuraishi et al, 1995;Inagaki et al, 2001;Green et al, 2006;Shimada and LaMotte, 2008). Histamine excites lamina I spinothalamic tract neurons in cats over a time course consistent with itch sensation (Andrew and Craig, 2001).…”

Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy

“…Interestingly, histamine-induced itching shows species-specificity. For example, histamine evokes scratching in most mouse strains but little in SpragueDawley rats [27,28] . It is well accepted that a specific sub-class of C-fibers mediates itch and is distinct from that mediating pain [29] .…”

The Role of the Mrgpr Receptor Family in Itch

“…Because patients experience itch when they first ingest chloroquine and because antihistamines do not effectively prevent this side effect, researchers in Africa concluded that chloroquine-induced itch is not an allergic response, nor is it mediated by histamine receptors (Abila et al 1994). Interestingly, injecting chloroquine into the skin of mice evokes a robust scratching response in the mice, and various inbred strains of mice exhibit different degrees of scratching responses (Green et al 2006). Based on this response, we tested whether our Mrgpr-cluster Δ À/À mice respond differently from wild-type following chloroquine injection.…”