Allergic Contact Dermatitis: A Model of Inflammatory Itch and Pain in Human and Mouse

Abstract

This chapter is an overview of published observations from our laboratory on the psychophysics and neurobiology of the persistent itch and pain of allergic contact dermatitis (ACD). ACD is a clinically significant problem with many features characteristic of other pruritic disorders. Our approach was to produce ACD experimentally in humans and in the mouse. The goal was to use the mouse as an animal model for investigating the peripheral neural mechanisms of itch and pain of ACD in humans. Humans and mice were each sensitized by cutaneous topical application of squaric acid dibutyl ester, a hapten not encountered in the environment. Subsequent challenge at another cutaneous site produced local inflammation (“ACD”) with humans reporting persistent itch (lasting up to a week) and mice exhibiting persistent itch- and pain-like behaviors directed toward the ACD site. Enhanced mechanically evoked itch and pain in surrounding skin in humans were reversibly blocked by numbing the ACD site with cold, suggesting dependence on ongoing activity from the site. In mice, in vivo recordings revealed spontaneous activity in a subset of pruriceptive, mechanoheat-sensitive nociceptors with unmyelinated axons innervating the ACD site. These and a larger subpopulation of acutely dissociated small-diameter neurons innervating the ACD site exhibited an upregulation of the receptor CXCR3 and excitatory responses to one of its ligands, the chemokine CXCL10 (IP-10) that contributes to the pathogenesis of ACD. Preliminary findings point to possible therapeutic targets that could be investigated in inflammatory itch disorders in humans.

Exploring neuronal mechanisms involved in the scratching behavior of a mouse model of allergic contact dermatitis by transcriptomics

“…We showed that repetitive oxazolone challenge on mouse cheek provokes both scratching (with hindpaw) and wiping (with forepaw) behavior, which could be interpreted as itch and pain sensation, respectively [13]. Consistent with our findings, studies from LaMotte's lab also found that the contact sensitizer squaric acid dibutyl ester-induced ACD model mice developed similar itch-and pain-related behaviors [2,38]. These studies support the notion that ACD model mice developed a mixed itch and pain sensation.…”

“…Allergic contact dermatitis is a type of skin disease involving overreactivity of skin to contact allergens, accompanied with skin inflammation and mixed pain and itch sensations [1][2][3][4]. ACD is triggered by sensitization and subsequent contact with allergens, which may originate from occupational, environmental, or nutritional sources [5].…”

Probing the force-from-lipid mechanism with synthetic polymers

“…Mechanosensitive channel activation sensitivity is an important feature of all mechanosensitive channels. Overactive mechanosensitive channels may lead to deleterious effects ranging from a loss in cell volume in bacteria or red blood cells (Cahalan et al, 2015; Levin and Blount, 2004) to persistent itch disease in higher organisms (LaMotte, 2016). Membrane composition has been increasingly shown to modulate the force-from-lipids activation of mechanosensitive channels and this effect is hypothesized to be due to changes in global membrane properties (Bruno et al, 2007).…”

Itch in Allergic Contact Dermatitis

“…ACD is also an example of diseases characterized by persistent itch in contrast to transient itch and accompanying nociceptor responses. Less is known about the nociceptor activity during itch lasting for days or longer ( 19 ).…”