Spinal cord NLRP1 inflammasome contributes to dry skin induced chronic itch in mice

Paeonol is a bioactive phenol presents mainly in Paeonia suffruticosa Andr. (Paeoniaceae), Paeonia lactiflora Pall., and Dioscorea japonica Thunb. (Dioscoreaceae), harboring various pharmacological activities including anti-inflammatory, antioxidant, immune regulatory activity and reverse chemoresistance. Recent reports revealed paeonol exhibited good effects on chronic dermatitis, such as atopic dermatitis (AD) and psoriasis. However, whether paeonol is effective for dry skin disease and its mechanism of action still remain unclear. In this study, we analysed the effects of paeonol on a mouse model of dry skin treated with acetone-ether-water (AEW), which showed impressive activities in reducing scratching behavior and skin inflammation. To elucidate the underlying molecular targets for the anti-pruritic ability of paeonol, we screened the expression of possible chemokine pathways in the spinal cord. The expression of CXCR3 was significantly alleviated by paeonol, which increased greatly in the spinal neurons of AEW mice. In addition, treatment of paeonol significantly inhibited AEW-induced expression of astrocyte activity-dependent genes including Tlr4, Lcn2 and Hspb1 et al. The inhibitory effects of paeonol on scratching behavior and astrocytic activation in the spinal cord induced by AEW were abolished when CXCR3 was antagonized or genetically ablated. Taken together, our results indicated that paeonol can ameliorate AEW-induced inflammatory response and itching behavior, and reduce the expression of spinal astrocyte activity-dependent genes induced by AEW, which are driven by CXCR3.

Download Full-text

Central opioid receptors mediate morphine-induced itch and chronic itch

10.1101/2020.05.31.126805 ◽

2020 ◽

Author(s):

Zilong Wang ◽

Changyu Jiang ◽

Hongyu Yao ◽

Ouyang Chen ◽

Sreya Rahman ◽

...

Keyword(s):

Spinal Cord ◽

Sensory Neurons ◽

Common Side Effect ◽

Cellular Mechanisms ◽

Conditional Deletion ◽

Outward Currents ◽

Clinical Pain ◽

Chronic Itch ◽

Allergic Contact

AbstractOpioids, such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal (i.t.) administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between µ-opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal (i.t.) opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that i.t. injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons (Oprm1-Vgat). Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 out of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons and suppressed evoked IPSCs in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by i.t. administration of NPY and abolished by spinal ablation of GRPR+ neurons, whereas i.t. GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the cutaneous T-cell lymphoma (CTCL) model, indicating a contribution of central MOR signaling to chronic itch. Our findings demonstrate that i.t. morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also suggest that chronic itch could be effectively treated with CNS-targeted naloxone.

Download Full-text

The Role of Transient Receptor Potential A1 and G Protein-Coupled Receptor 39 in Zinc-Mediated Acute and Chronic Itch in Mice

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.768731 ◽

2022 ◽

Vol 14 ◽

Author(s):

Yue Hu ◽

Qing-Yue Fu ◽

Dan-Ni Fu ◽

Xue-Long Wang ◽

Zhi-Hong Wang ◽

...

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Systemic Administration ◽

Common Symptom ◽

Dry Skin ◽

C Fibers ◽

Transient Receptor Potential A1 ◽

Chronic Itch ◽

Transient Receptor

Itching is a common symptom of many skin or systemic diseases and has a negative impact on the quality of life. Zinc, one of the most important trace elements in an organism, plays an important role in the regulation of pain. Whether and how zinc regulates itching is largely unclear. Herein, we explored the role of Zn2+ in the regulation of acute and chronic itch in mice. It is found that intradermal injection (i.d.) of Zn2+ dose-dependently induced acute itch and transient receptor potential A1 (TRPA1) participated in Zn2+-induced acute itch in mice. Moreover, the pharmacological analysis showed the involvement of histamine, mast cells, opioid receptors, and capsaicin-sensitive C-fibers in Zn2+-induced acute itch in mice. Systemic administration of Zn2+ chelators, such as N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), pyrithione, and clioquinol were able to attenuate both acute itch and dry skin-induced chronic itch in mice. Quantitative polymerase chain reaction (Q-PCR) analysis showed that the messenger RNA (mRNA) expression levels of zinc transporters (ZIPs and ZnTs) significantly changed in the dorsal root ganglia (DRG) under dry skin-induced chronic itch condition in mice. Activation of extracellular signal-regulated kinase (ERK) pathway was induced in the DRG and skin by the administration of zinc or under dry skin condition, which was inhibited by systemic administration of Zn2+ chelators. Finally, we found that the expression of GPR39 (a zinc-sensing GPCR) was significantly upregulated in the dry skin mice model and involved in the pathogenesis of chronic itch. Together, these results indicated that the TRPA1/GPR39/ERK axis mediated the zinc-induced itch and, thus, targeting zinc signaling may be a promising strategy for anti-itch therapy.

Download Full-text

Enhanced responses of lumbar superficial dorsal horn neurons to intradermal PAR-2 agonist but not histamine in a mouse hindpaw dry skin itch model

Journal of Neurophysiology ◽

10.1152/jn.01124.2010 ◽

2011 ◽

Vol 105 (6) ◽

pp. 2811-2817 ◽

Cited By ~ 16

Author(s):

Tasuku Akiyama ◽

Mirela Iodi Carstens ◽

E. Carstens

Keyword(s):

Spontaneous Activity ◽

Dorsal Horn ◽

Allyl Isothiocyanate ◽

Skin Condition ◽

Intradermal Injection ◽

Neural Pathways ◽

Mechanical Stimuli ◽

Superficial Dorsal Horn ◽

Dry Skin ◽

Chronic Itch

Chronic itch is symptomatic of many skin conditions and systemic diseases. Little is known about pathophysiological alterations in itch-signaling neural pathways associated with chronic itch. We used a mouse model of hindpaw chronic dry skin itch to investigate properties of presumptive itch-signaling neurons. Neurons in the lumbar superficial dorsal horn ipsilateral to hindpaw dry skin treatment exhibited a high level of spontaneous activity that was inhibited by scratching the plantar surface. Most spontaneously active units exhibited further increases in firing rate following intradermal injection of an agonist of the protease-activated receptor PAR-2, or histamine. The large majority of pruritogen-responsive units also responded to capsaicin and allyl isothiocyanate. For neurons ipsilateral to dry skin treatment, responses elicited by the PAR-2 agonist, but not histamine or mechanical stimuli, were significantly larger compared with neurons ipsilateral to vehicle (water) treatment or neurons recorded in naïve (untreated) mice. The spontaneous activity may signal ongoing itch, while enhanced PAR-2 agonist-evoked responses may underlie hyperknesis (enhanced itch), both of which are symptomatic of many chronic itch conditions. The enhancement of neuronal responses evoked by the PAR-2 agonist, but not by histamine or mechanical stimuli, implies that the dry skin condition selectively sensitized PAR-2 agonist-sensitive primary afferent pruriceptors.

Download Full-text

Novel TRPM8 agonist cooling compound against chronic itch: results from a randomized, double-blind, controlled, pilot study in dry skin

Journal of the European Academy of Dermatology and Venereology ◽

10.1111/jdv.14041 ◽

2016 ◽

Vol 31 (6) ◽

pp. 1064-1068 ◽

Cited By ~ 17

Author(s):

S. Ständer ◽

M. Augustin ◽

D. Roggenkamp ◽

C. Blome ◽

T. Heitkemper ◽

...

Keyword(s):

Pilot Study ◽

Dry Skin ◽

Double Blind ◽

Chronic Itch

Download Full-text

The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2022087118 ◽

2021 ◽

Vol 118 (13) ◽

pp. e2022087118

Author(s):

Tiphaine Voisin ◽

Caroline Perner ◽

Marie-Angele Messou ◽

Stephanie Shiers ◽

Saltanat Ualiyeva ◽

...

Keyword(s):

Molecular Mechanisms ◽

Skin Diseases ◽

Chronic Phase ◽

Drg Neurons ◽

Dry Skin ◽

Chronic Itch ◽

Allergic Skin ◽

Dose Dependent ◽

Type 2 Inflammation

Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2−/− mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.

Download Full-text