Acta Pharmacol Sin 2018 Mar;39(3):331-335.

 doi: 10.1038/aps.2017.152. Epub 2017 Nov 2.

A pivotal role for the activation of TRPV3 channel in itch sensations induced by the natural skin sensitizer carvacrol

Ting-Ting Cui ¹, Gong-Xin Wang ¹, Ning-Ning Wei ¹, KeWei Wang ¹

• PMID: 29094727
• PMCID: PMC5843833
• DOI: 10.1038/aps.2017.152

Abstract

Itching is an intricate, common symptom of dermatologic and systemic diseases, and both TRPV3 and TRPA1 channels have been suggested to function as downstream effector targets. But the relative contributions of TRPV3 and TRPA1 to itch sensation in vivo remain unclear. To dissect the role of TRPA1 or TRPV3 in the cutaneous sensation of itching, we took the advantage of a natural compound carvacrol from oregano, and examined its effect on the induction of scratching behavior in mice. We showed that the intradermal injection of carvacrol (0.01%, 0.1% and 1%, 50 μL) induced scratching in a concentration-dependent manner. But in TRPV3-knockout mice, the scratching induced by carvacrol (1%, 50 μL) was markedly decreased by approximately 64% (from 275 scratching bouts down to 90) within 60 min. Further analysis revealed that TRPV3-knockout caused a reduction of scratching bouts for approximately 40% in the first 20 min (the initial phase), whereas the scratching bouts were reduced by approximately 90% in the last 40 min (the sustained phase). These results were in consistence with those in our whole-cell recordings in HEK-293T cells expressing either TRPA1 or TRPV3: carvacrol exhibited similar potencies in activating either TRPA1 or TRPV3, but carvacrol-activated TRPA1 current showed a rapid desensitization, which was reduced by approximately 90% within 5 min before a complete washout, whereas carvacrol-induced TRPV3 current showed a slow desensitization that caused less than 30% of current reduction in 10 min and left a significant residual TRPV3 current after washout. Our results demonstrate that carvacrol from plant oregano is a skin sensitizer or allergen; TRPV3 is involved in the initial phase and the sustained phase of pruritus, whereas TRPA1 likely contributes to the initial phase.

J Ethnopharmacol 2025 Jan 30;337(Pt 2):118882.

 doi: 10.1016/j.jep.2024.118882. Epub 2024 Oct 2.

Investigation of the anti-inflammatory, anti-pruritic, and analgesic effects of sophocarpine inhibiting TRP channels in a mouse model of inflammatory itch and pain

Hekun Zeng ¹, Zhe Zhang ², Dan Zhou ³, Ranjing Wang ⁴, Alexei Verkhratsky ⁵, Hong Nie ⁶

• PMID: 39366497
• DOI: 10.1016/j.jep.2024.118882

Abstract

Ethnopharmacological relevance: Sophocarpine is a bioactive compound extracted from the dried root of Sophorae Flavesentis Aiton, a plant that has been used for thousands of years for various conditions including skin itch and pain. Its antipruritic and analgesic effects are suggested in publications, while the molecular mechanisms underneath interacting with TRP channels are not understood.

Aim of the study: We investigated the anti-inflammatory, antipruritic, and analgesic effects of sophocarpine in a murine inflammatory itch and pain model to elucidate the underlying mechanisms.

Materials and methods: We evaluated sophocarpine’s anti-pruritic and analgesic effects by monitoring mice’s scratching and wiping behaviors, and the anti-inflammatory effect by measuring psoriasis area and severity index (PASI) score. The mRNA and protein expression of TRPA1/TRPV1 was analyzed by real-time quantitative polymerase chain reaction and western blotting. We further investigated the relationship between sophocarpine and TRPA1/TRPV1 in mice administered allyl-isothiocyanate (AITC) or capsaicin and by molecular docking.

Results: We found that sophocarpine decreased scratching bouts, wipes, and the PASI score, reduced the TNF-α and IL-1β in the skin and TRPA1 and TRPV1 in the trigeminal ganglion. Pretreatment of sophocarpine decreased AITC-induced scratching bouts and wipes and capsaicin-induced wipes. We also found potential competitive bindings between sophocarpine and AITC/capsaicin to TRPA1/TRPV1.

Conclusions: Sophocarpine is a potential competitive inhibitor of TRPA1 and TRPV1 channels eliciting strong anti-inflammatory, anti-pruritic, and analgesic effects, suggesting its significant therapeutic potential in treating diseases with inflammatory itch and pain.

Keywords: Analgesic; Anti-inflammatory; Anti-pruritic; Sophocarpine; TRPA1; TRPV1.

Sci Adv 2024 Sep 27;10(39):eadp6038. doi: 10.1126/sciadv.adp6038. Epub 2024 Sep 25.

Kappa opioids inhibit spinal output neurons to suppress itch

Tayler D Sheahan ¹, Charles A Warwick ¹, Abby Y Cui ¹, David A A Baranger ², Vijay J Perry ¹, Kelly M Smith ¹, Allison P Manalo ¹, Eileen K Nguyen ¹, H Richard Koerber ¹, Sarah E Ross ^1 3

• PMID: 39321286
• PMCID: PMC11423883
• DOI: 10.1126/sciadv.adp6038

Abstract

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural basis for itch remains unclear. Here, we used two-photon Ca²⁺ imaging of the dorsal horn to visualize neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal interneurons recruited by diverse itch-causing stimuli that represents a subset of neurons that express the gastrin-releasing peptide receptor (GRPR). Moreover, we find that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nuclei. We then show that the kappa opioid receptor agonist nalfurafine relieves itch by selectively inhibiting GRPR spinoparabrachial neurons. These experiments provide a population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.

The fungal secretory peptide micasin induces itch by activating MRGPRX1/C11/A1 on peripheral neurons

Haifeng Yang ¹, Yian Chen ², Luyao Wang ², Bing Gan ³, Leiye Yu ³, Ruobing Ren ³, Hang Fai Kwok ⁴, Yingliang Wu ², Zhijian Cao ⁵

J Invest Dermatol. 2024 Jun 28:S0022-202X(24)01871-2.

PMID: 38945438
DOI: 10.1016/j.jid.2024.05.031

Abstract

Pruritus is the leading symptom of dermatophytosis. Microsporium canis is one of the predominant dermatophytes causing dermatophytosis. However, the pruritogenic agents and the related molecular mechanisms of the dermatophyte M. canis remain poorly understood. Here, the secretion of the dermatophyte M. canis was found to dose-dependently evoke itch in mice. The fungal peptide micasin secreted from M. canis was then identified to elicit mouse significant scratching and itching responses. The peptide micasin was further revealed to directly activate mouse dorsal root ganglia (DRG) neurons to mediate the non-histaminergic itch. Knockout and antagonistic experiments demonstrated that MRGPRX1/C11/A1 rather than MRGPRX2/b2 activated by micasin contributed to pruritus. The chimera and mutation of MRGPRX1 showed that three domains (ECL3, TMH3 and TMH6) and four hydrophobic residues (Y99, F237, L240 and W241) of MRGPRX1 played the key role in micasin-triggered MRGPRX1 activation. Our study sheds light on the dermatophytosis-associated pruritus and may provide potential therapeutic targets and strategies against pruritus caused by dermatophytes.

Keywords: Dermatophytosis; Fungal defensin; Itch; Microsporium canis; Mrgprs.

Pain. 2024 Feb 28.  doi: 10.1097/j.pain.0000000000003189.

ATF4 inhibits TRPV4 function and controls itch perception in rodents and nonhuman primate

Man-Xiu Xie ¹, Jun-Hua Rao ², Xiao-Yu Tian ³, Jin-Kun Liu ^3 4, Xiao Li ⁵, Zi-Yi Chen ⁶, Yan Cao ⁵, An-Nan Chen ⁶, Hai-Hua Shu ⁷, Xiao-Long Zhang 

• PMID: 38422489
• DOI: 10.1097/j.pain.0000000000003189

Abstract

Acute and chronic itch are prevalent and incapacitating, yet the neural mechanisms underlying both acute and chronic itch are just starting to be unraveled. Activated transcription factor 4 (ATF4) belongs to the ATF/CREB transcription factor family and primarily participates in the regulation of gene transcription. Our previous study has demonstrated that ATF4 is expressed in sensory neurons. Nevertheless, the role of ATF4 in itch sensation remains poorly understood. Here, we demonstrate that ATF4 plays a significant role in regulating itch sensation. The absence of ATF4 in dorsal root ganglion (DRG) neurons enhances the itch sensitivity of mice. Overexpression of ATF4 in sensory neurons significantly alleviates the acute and chronic pruritus in mice. Furthermore, ATF4 interacts with the transient receptor potential cation channel subfamily V member 4 (TRPV4) and inhibits its function without altering the expression or membrane trafficking of TRPV4 in sensory neurons. In addition, interference with ATF4 increases the itch sensitivity in nonhuman primates and enhances TRPV4 currents in nonhuman primates DRG neurons; ATF4 and TRPV4 also co-expresses in human sensory neurons. Our data demonstrate that ATF4 controls pruritus by regulating TRPV4 signaling through a nontranscriptional mechanism and identifies a potential new strategy for the treatment of pathological pruritus.

Cav3.2 T-type calcium channel mediates acute itch and contributes to chronic itch and inflammation in experimental atopic dermatitis

Ji-Woong Ahn ¹, Song-Ee Kim ², Do-Young Kim ³, Inhye Jeong ², Sohyun Kim ¹, Seungsoo Chung ⁴, Sang Eun Lee ⁵

• PMID: 37863387
• DOI: 10.1016/j.jid.2023.07.029

Abstract

Voltage-gated calcium channels regulate neuronal excitability. The Cav3.2 isoform of the T-type voltage-activated calcium channel is expressed in sensory neurons and is implicated in pain transmission. However, its role in itch remains unclear. Herein, we demonstrated that Cav3.2 is expressed by mechanosensory and peptidergic subsets of mouse dorsal root ganglion (DRG) neurons and colocalized with TRPV1 and receptors for type 2 cytokines. Cav3.2-positive neurons innervate human skin. A deficiency of Cav3.2 reduces histamine, IL-4/IL-13, and thymic stromal lymphopoietin-induced itch in mice. Cav3.2 channels were upregulated in the DRGs of an atopic dermatitis (AD)-like mouse model and mediated neuronal excitability. Genetic knockout of Cav3.2 or T-type calcium channel blocker mibefradil treatment reduced spontaneous and mechanically induced scratching behaviors and skin inflammation in an AD-like mouse model. Substance P and vasoactive intestinal polypeptide levels were increased in the trigeminal ganglia (TG) from AD-like mouse model, and genetic ablation or pharmacological inhibition of Cav3.2 reduced their gene expression. Cav3.2 knockout also attenuated the pathologic changes in ex vivo skin explants co-cultured with TG neurons from AD-induced mice. Our study identifies the role of Cav3.2 in both histaminergic and non-histaminergic acute itch. Cav3.2 channel also contributes to AD-related chronic itch and neuroinflammation.

Keywords: Cav3.2; T-type voltage-activated calcium channel; atopic dermatitis; itch; neuroinflammation; substance P; vasoactive intestinal polypeptide.

Nat Commun. 2023 Apr 29;14(1):2478. doi: 10.1038/s41467-023-38209-x.

Yuanbo Jia ^# 1 2, Jiahui Hu ^# 2 3, Keli An ^1 2, Qiang Zhao ^2 3, Yang Dang ^2 3, Hao Liu ^1 2, Zhao Wei ^1 2, Songmei Geng ⁴, Feng Xu ^5 6

• PMID: 37120459
• PMCID: PMC10148840
• DOI: 10.1038/s41467-023-38209-x

Abstract

Atopic dermatitis (AD) is a chronic skin disease caused by skin immune dyshomeostasis and accompanied by severe pruritus. Although oxidative stress and mechanical scratching can aggravate AD inflammation, treatment targeting scratching is often overlooked, and the efficiency of mechano-chemically synergistic therapy remains unclear. Here, we find that enhanced phosphorylation of focal adhesion kinase (FAK) is associated with scratch-exacerbated AD. We then develop a multifunctional hydrogel dressing that integrates oxidative stress modulation with FAK inhibition to synergistically treat AD. We show that the adhesive, self-healing and antimicrobial hydrogel is suitable for the unique scratching and bacterial environment of AD skin. We demonstrate that it can scavenge intracellular reactive oxygen species and reduce mechanically induced intercellular junction deficiency and inflammation. Furthermore, in mouse AD models with controlled scratching, we find that the hydrogel alleviates AD symptoms, rebuilds the skin barrier, and inhibits inflammation. These results suggest that the hydrogel integrating reactive oxygen species scavenging and FAK inhibition could serve as a promising skin dressing for synergistic AD treatment.