Brain allopregnanolone induces marked scratching behaviour in diet-induced atopic dermatitis mouse model

Abstract

Allopregnanolone (ALLO) is a neurosteroid produced in the brain, but so far, no study has explored its link with itching. Herein, we used a diet-induced atopic dermatitis mouse model to examine whether exogenously administered and endogenously produced ALLO contribute to inducing scratching. Systemic administration of ALLO elicited robust scratching in the atopic dermatitis model, while it did not affect spontaneous and pruritogen-induced scratching in normal mice. ALLO caused scratching when administered intracisternally, but not when administered intrathecally or intradermally, suggesting the involvement of supraspinal mechanisms. Pharmacological analyses suggested that both γ-aminobutyric acid type A receptor activation and serotonin type 3 receptor inhibition were involved in ALLO-induced scratching. We next examined whether endogenously produced ALLO is involved in ethanol-induced scratching in atopic dermatitis mice, because ethanol administration increases ALLO in rodent brain. Acute ethanol administration increased brain ALLO levels, which coincided with increased scratching. Pre-treatment with finasteride, a synthetic ALLO inhibitor, suppressed ethanol-induced scratching and ALLO production in the brain. Collectively, our results demonstrated for the first time that ALLO administration caused marked scratching in atopic dermatitis mice, and ethanol-induced scratching may be mediated through endogenously produced brain ALLO.

miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus

QingjianHan¹⁴DiLiu¹⁴MarinoConvertino²ZilongWang¹ChangyuJiang¹Yong HoKim¹XinLuo¹XinZhang¹AndreaNackley¹Nikolay V.Dokholyan²⁵Ru-RongJi¹³⁶

Summary

Increasing evidence suggests that extracellular miRNAs may serve as biomarkers of diseases, but the physiological relevance of extracellular 
miRNA  is unclear. We find that intradermal cheek injection of miR-711 induces TRPA1-depedent itch (scratching) without pain (wiping) in naive mice. Extracellular perfusion of miR-711 induces TRPA1 currents in both Trpa1-expressing heterologous cells and native sensory neurons through the core sequence GGGACCC. Computer simulations reveal that the core sequence binds several residues at the extracellular S5-S6 loop of TRPA1, which are critical for TRPA1 activation by miR-711 but not allyl isothiocyanate. Intradermal inoculation of human Myla cells induces lymphoma and chronic itch in immune-deficient mice, associated with increased serum levels of miR-711, secreted from cancer cells. Lymphoma-induced chronic itch is suppressed by miR-711 inhibitor and a blocking peptide that disrupts the miR-711/TRPA1 interaction. Our findings demonstrated an unconventional physiological role of extracellular naked miRNAs as itch mediators and ion channel modulators.

Abstract

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch– and chronic itch–challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting 15% to 20% of the general population in developed countries.¹ It is characterized by recurrent eczematous legions and intense itch. Because the itch sensation induces scratching behavior, which exacerbates the skin inflammation and disturbs the quality of life of affected individuals, chronic itch is a challenging clinical problem in the treatment of AD.

Itch can be induced by various chemical mediators. Among them, much attention has been paid to IL-31 as an AD-associated itch mediator since the discovery of the pruritogenic action of IL-31 in mice.² IL-31 is mainly produced by CD4⁺ T cells and transmits the signals via a heterodimeric receptor composed of IL-31 receptor A and oncostatin M receptor (OSMR), both of which are expressed in various cell types including dorsal root ganglion (DRG) neurons.³ A recent clinical study has demonstrated that blockade of IL-31 signals by a specific antibody for IL-31 receptor A alleviates pruritus in patients with AD.⁴ However, the neuronal mechanism underlying IL-31–induced itch sensation is poorly understood.

Peripheral sensitisation and loss of descending inhibition is a
hallmark of chronic pruritus

Neurophysiological mechanisms leading to chronicity of pruritus are not yet fully understood and it is not known whether these mechanisms diverge between different underlying diseases of chronic pruritus. This study aimed to detect such mechanisms in chronic pruritus of various origins. One-hundred and twenty patients with chronic pruritus of inflammatory origin (atopic dermatitis), neuropathic origin (brachioradial pruritus) and chronic prurigo of nodular type, the latter as a model for chronic scratching, as well as 40 matched healthy controls participated in this study. Stimulation with cowhage induced a more intensive itch sensation compared to stimulation with other substances in all patient groups but not in healthy controls, arguing for sensitisation of cutaneous mechano- and heat-sensitive C-fibers in chronic pruritus. All patient groups showed a decreased intraepidermal nerve fibre density compared to controls. A decreased condition pain modulation effect was observed in all patient groups compared to controls, suggesting a reduced descending inhibitory system in chronic pruritus. In sum, chronic pruritus of different etiology showed a mixed peripheral and central pattern of neuronal alterations, which might contribute to the chronicity of pruritus with no differences between pruritus entities. Our
findings may contribute to the development of future treatment strategies targeting these pathomechanisms.

Key words: Itch, quantitative sensory testing, conditioned pain modulation,
intraepidermal nerve fibre density, pain