Itch

Intractable or recurrent chronic itch greatly reduces the patients' quality of life and impairs their daily activities. In this study, we investigated whether there are certain key signaling molecules downstream of the recently identified peptides mediating itch in the spinal cord. RNA sequencing analysis of mouse spinal cord in chronic itch models induced by squaric acid dibutylester and imiquimod showed that extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is the most significantly up-regulated gene cluster in both models. In four different mouse models of chronic itch, sustained ERK phosphorylation was detected mainly in spinal neurons, and MEK inhibitors significantly inhibited chronic itch in these models. Phosphorylated ERK (pERK) was observed in interneurons expressing receptors of different neuropeptides for itch, including GRPR, NPRA, NMBR or sst. Blocking GRPR and NPRA by genetic approaches or toxins in mice significantly attenuated or ablated spinal pERK. When HEK293T cells transfected with these receptors were exposed to their respective agonists, ERK was the most significantly activated intracellular signaling molecule. Together, our work showed that pERK is a unique marker for itch signal transmission in the spinal cord and an attractive target for the treatment of chronic itch.

This study discovered a novel neuro-epidermal BNP-TRPV3-Serpin E1-mediated pathway in severe atopic dermatitis (AD). Serpin E1 was identified as a new itch-inducer. We propose this pathway represents an important target for the treatment of AD.

An itch is defined as an unpleasant sensation that evokes a desire to scratch. Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system and has a crucial role in pruriceptive processing in the spinal dorsal horn. It is well known that glutamate exerts its effects by binding to various glutamate receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and that AMPA/kainate receptors play a crucial role in pruriceptive processing; however, the precise role of AMPA receptors remains uncertain. Perampanel, an antiepileptic drug, is an antagonist of AMPA receptors. Pretreatment with perampanel dose-dependently attenuated the induction of scratching, a behavior typically associated with pruritus, by intradermal administration of the pruritogen chloroquine. In addition, the induction of scratching in mice painted with diphenylcyclopropenone and NC/Nga mice treated with Biostir AD, animal models of contact dermatitis and atopic dermatitis, respectively, was dose-dependently alleviated by administration of perampanel. These findings indicate that AMPA receptors play a crucial role in pruriceptive processing in mice with acute or chronic pruritus.

Accumulating evidence has highlighted the essential roles of cytokines in itch processing. Although IL-23 and Th17 cytokines are elevated in inflammatory skin disorders, their role in itch is unknown. Here we investigated the role of IL-23 and IL-17A in itch response using an in vitro calcium imaging of mouse dorsal root ganglion (DRG) neurons and an in vivo behavior test. Calcium imaging studies revealed that a few DRG neurons (~5%) responded to either IL-23 or IL-17A. Pre-treatment cells with IL-23 significantly reduced calcium responses to histamine and capsaicin but not chloroquine. Behavior experiments showed neither IL-23 nor IL-17A evoked scratching. IL-23 significantly decreased histamine-evoked scratching without affecting chloroquine-evoked scratching. There was no difference in scratching between IL-17A- and vehicle-treated groups. These results indicate that IL-23 might play a role in regulating histaminergic itch via modulation of TRPV1 activity.

Acute itch is elicited by histamine, as well as non-histaminergic itch mediators including chloroquine, BAM8-22 and SLIGRL. When injected intradermally, histamine binds to histamine H1 and H4 receptors that activate TRPV1 to depolarize pruriceptors. Chloroquine, BAM-822, and SLIGRL respectively bind to Mas-related G-protein-coupled receptors MrgprA3, MrgprC11, and MrgprC11/PAR2 that in turn activate TRPA1. In this study we tested if histamine, chloroquine, BAM8-22 and SLIGRL elicit thermal hyperalgesia and mechanical allodynia in adult male mice. We measured the latency of hindpaw withdrawal from a noxious heat stimulus, and the threshold for hindpaw withdrawal from a von Frey mechanical stimulus. Intraplantar injection of histamine resulted in significant thermal hyperalgesia (p<0.01) and mechanical allodynia (p<0.0001) ipsilaterally that persisted for 1 hr. Pretreatment with the TRPV1 antagonist AMG-517 (10 or 20 μg), but not the TRPA1 antagonist HC-030031 (50 or 100 μg), significantly attenuated the magnitude and time course of thermal hyperalgesia and mechanical allodynia elicited by histamine (p<0.0001 for both), indicating that these effects are mediated by TRPV1. In contrast, pretreatment with the TRPA1 antagonist significantly reduced thermal hyperalgesia and mechanical allodynia elicited by chloroquine (p<0.001 and, p<0.0001, respectively), BAM-822 (p<0.01, p<0.001, respectively) and SLGRL (p<0.05, p<0.001, respectively), indicating that effects elicited by these non-histaminergic itch mediators require TRPA1. TRPV1 and TRPA1 channel inhibitors thus may have potential use in reducing hyperalgesia and allodynia associated with histaminergic and non-histaminergic itch, respectively.