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. 2023 Jul 12;24(14):11380. doi: 10.3390/ijms241411380

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© 2023 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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(a) Pyschosomatic aspect of the itch–scratch cycle in atopic dermatitis. This cycle disrupts the epidermal barrier, causes damage to keratinocytes, activates local dendritic cells, and triggers the adaptive response. Exogenous pruritogens like allergens, pathogens, toxins, and irritants, as well as endogenous pruritogens like cytokines, neuropeptides, signaling lipids, and proteases released from keratinocytes and immune cells, bind to receptors on cutaneous itch sensory neurons. These sensory neurons, primarily composed of unmyelinated C-fibers, transmit the itch sensation as action potentials to specific dorsal root ganglia and the central nervous system. The binding of mediators to their respective receptors initiates a signaling cascade involving secondary messengers, which activate TRP family cation channels (particularly TRPA and TRPV), ultimately leading to the opening of voltage-gated sodium channels and neuronal depolarization. Na⁺, sodium ion; Ca⁺, calcium ion; H4R, Histamine 4 receptor; CB1R, Cannabinoid type 1 receptor; CB2R, Cannabinoid type 2 receptor; NK1R, neurokinin 1 receptor; PAR2, Protease-activated receptor 2; S1PR, Sphingosine-1-phosphate receptor; P2X, purinoreceptors 3 (P2XR3); TRPA1, Transient receptor cation ankyrin 1; TRPV1, Transient receptor potential channel vanilloid 1; TRPV3, Transient receptor potential channel vanilloid 3. This figure was created with Biorender at www.biorender.com. (b) Mechanism of action of different drugs acting on various receptors expressed in the sensory neuron responsible for the pruritus in atopic dermatitis. JNJ 39758979, adriforant, and LEO 152020 are H4R antagonists. S-777469 is a CB2R agonist. Tradipitant and selropitant are NK1R antagonists. Methylbenzyl methylbenzimidazole piperidinyl methanone (MMP) is a selective PAR-2 inhibitor. KRO-105714 is a dual antagonist of sphingosylphosphorylcholine and sphingosine-1-phosphate receptor 1 in topical form. JTE-013 is an S1PR2 antagonist in topical form. Etrasimod is an oral S1PR modulator. SCD-044 is an S1PR1 agonist. A317491 and BLU-5937 are selective P2XR3 antagonists. HC-030031 is a topical TRPA1 antagonist while GRC17536 is an oral TRPA1 antagonist. PAC-14028, CT327/SNA-120, and asivatrep are all TRPV1 antagonists. Na⁺, sodium ion; Ca⁺, calcium ion; H4R, Histamine 4 receptor; CB1R, Cannabinoid type 1 receptor; CB2R, Cannabinoid type 2 receptor; NK1R, neurokinin 1 receptor; PAR2, Protease-activated receptor 2; S1PR, Sphingosine-1-phosphate receptor; P2X purinoreceptors 3, P2XR3; TRPA1, Transient receptor cation ankyrin 1; TRPV1, Transient receptor potential channel vanilloid 1; TRPV3, Transient receptor potential channel vanilloid 3. This figure was created with Biorender at www.biorender.com.