Itch Processing in the Skin

Abstract

Itching can result from activity of specialized primary afferent neurons (“pruriceptors”) that have been shown to express certain molecular markers such as B-type natriuretic peptide and several members of the Mrgpr-family in rodents. On the other hand, neurons involved in pain processing (“nociceptors”) can also provoke itching when the activation site is restricted to an isolated tiny spot within the epidermis. Individuals classified as having sensitive skin report increased itching and pain sensations upon weak external stimuli that are not painful or itchy in the control group. Numerous possible factors could contribute to sensitive skin along the pathway of transduction of the external stimuli into peripheral neuronal signals, followed by neuronal processing, finally resulting in the perception: (a) reduced local protective factors leading to impaired skin barrier function, (b) increased production of excitatory skin mediators, (c) sensitized peripheral neurons, (d) facilitated spinal and central processing, and (e) reduced descending inhibition from the central nervous system. For all of those pathophysiological mechanisms there are clinical examples such as atopic dermatitis (a,b,c), neuropathic itching (c,e), and restless leg syndrome (d,e). However, none of these factors have been directly linked to the occurrence of sensitive skin. Moreover, individuals reporting sensitive skin are heterogeneous and a subpopulation with defined pathophysiology has not yet been identified. Given that the condition is reported in about 50% of women, and thereby includes many healthy individuals, it appears problematic to assign a definitive pathophysiological mechanism to it.

Involvement of Neuro-Immune Interactions in Pruritus With Special Focus on Receptor Expressions

“…However, the MRGPRs can be activated by various endogenous and exogenous peptides or molecules, such as antimicrobial host defense or opioid peptides, SP or eosinophilic granules, but also by drugs like vancomycin or chloroquine (CQ) ( 12 , 207 ). Particularly, MRGPRA3 and MRGPRC11 in mice as well as the human ortholog MRGPRX1 got into the focus of pruritus researchers over the past decade ( 12 , 208 ). It was shown that CQ activated MRGPRA3 leading to a pruritus signal via the activation of TRPA1 ( 24 ).…”

The Neuropathic Itch Caused by Pseudorabies Virus

“…In the case of a pruriceptive itch, skin inflammation results in the recruitment and activation of immune cells to the skin epithelium. Activated immune cells release pro-inflammatory mediators, such as interleukin (IL) 31 and IL-33 that sensitize pruriceptors, leading to peripheral sensitization and activation of itch signaling pathways [121]. In the case of a neuropathic itch, peripheral nerve injury can cause inflammation of the nervous system, so called neuroinflammation.…”

Dialog between skin and its microbiota: Emergence of “Cutaneous Bacterial Endocrinology”

“…A particular attention should be given to γ‐aminobutyric acid (GABA) which in skin is produced by fibroblasts [ 88 ] and immune cells, [ 89 ] and released by interneurons involved itch transmission. [ 58 ] GABA exerts multiple local effects in skin, including fibroblasts proliferation and regulation of collagen I expression. [ 90,91 ] However, GABA is also known as a universal inter‐kingdom communication molecule.…”

“…[ 57 ] More recently, the study of itch revealed that BNP present by skin primary sensory afferent fibres should be a key mediator in a specific itch neurotransmission pathway. [ 58 ] Natriuretic peptides, and especially CNP, are also produced locally by endothelial cells and ANP, synthesized by cardiomyocytes, is circulating in blood as an hormone. [ 56 ] In this regard, in skin the bulge of the hair follicle is a region of special interest because of the presence of a dense network of capillary vessels at the immediate vicinity of the hair follicle hollow [ 59 ] where gland ducts open to a rich microbial community.…”