Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons

Palkar, Radhika; Ongun, Serra; Catich, Edward; Li, Natalie; Borad, Neil; Sarkisian, Angela; McKemy, David D.

doi:10.1016/j.jid.2017.12.025

Cited by 65 publications

(58 citation statements)

References 46 publications

(84 reference statements)

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“…Indeed, it has been shown that TRPM8-expressing DRG neurons are required for inhibition of itch by cooling and furthermore, that topical application of menthol inhibits chloroquine-evoked itch behaviors (Palkar et al, 2018). Thus, targeting TTX-sensitive Na V 1.1 channels in mentholsensitive DRG neurons might prove to be a new direction for the treatment of various sensory disorders.…”

Section: Discussionmentioning

confidence: 99%

Tetrodotoxin-sensitive sodium channels mediate action potential firing and excitability in menthol-sensitive Vglut3-lineage sensory neurons

Griffith

Docter

Lumpkin

2019

Preprint

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Small-diameter vesicular glutamate transporter 3-lineage (Vglut3 lineage ) dorsal root ganglion (DRG) neurons play an important role in mechanosensation and thermal hypersensitivity; however, little is known about their intrinsic electrical properties. We therefore set out to investigate mechanisms of excitability within this population. Calcium microfluorimetry analysis of male and female mouse DRG neurons demonstrated that the cooling compound menthol selectively activates a subset of Vglut3 lineage neurons. Whole-cell recordings showed that smalldiameter Vglut3 lineage DRG neurons fire menthol-evoked action potentials and exhibited robust, transient receptor potential melastatin 8 (TRPM8)-dependent discharges at room temperature.This heightened excitability was confirmed by current-clamp and action potential phase-plot analyses, which showed menthol-sensitive Vglut3 lineage neurons to have more depolarized membrane potentials, lower firing thresholds, and higher evoked firing frequencies compared with menthol-insensitive Vglut3 lineage neurons. A biophysical analysis revealed voltage-gated sodium channel (Na V ) currents in menthol-sensitive Vglut3 lineage neurons were resistant to entry into slow inactivation compared with menthol-insensitive neurons. Multiplex in situ hybridization showed similar distributions of tetrodotoxin (TTX)-sensitive Na V s transcripts between TRPM8positive and -negative Vglut3 lineage neurons; however, Na V 1.8 transcripts, which encode TTXresistant channels, were more prevalent in TRPM8-negative neurons. Conversely, pharmacological analyses identified distinct functional contributions of Na V subunits, with Na V 1.1 driving firing in menthol-sensitive neurons, whereas other small-diameter Vglut3 lineage neurons rely primarily on TTX-resistant Na V channels. Additionally, when Na V 1.1 channels were blocked, the remaining Na V currents readily entered into slow inactivation in menthol-sensitive Vglut3 lineage neurons. Thus, these data demonstrate that TTX-sensitive Na V s drive action potential firing in menthol-sensitive sensory neurons and contribute to their heightened excitability. Significance StatementSomatosensensory neurons encode various sensory modalities including thermoreception, mechanoreception, nociception and itch. This report identifies a previously unknown requirement for tetrodotoxin-sensitive sodium channels in action potential firing in a discrete subpopulation of small-diameter sensory neurons that are activated by the cooling agent menthol. Together, our results provide a mechanistic understanding of factors that control intrinsic excitability in functionally distinct subsets of peripheral neurons. Furthermore, as menthol has been used for centuries as an analgesic and anti-pruritic, these findings support the viability of Na V 1.1 as a therapeutic target for sensory disorders.

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Section: Discussionmentioning

confidence: 99%

Tetrodotoxin-sensitive sodium channels mediate action potential firing and excitability in menthol-sensitive Vglut3-lineage sensory neurons

Griffith

Docter

Lumpkin

2019

Preprint

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“…Mechanical stimuli, pain (conveyed by TRPV1 and TRPA1 positive nerves), and cooling (transduced through transient receptor potential melastatin [TRPM] 8 positive nerves) can attenuate itch sensation. [49][50][51] These sensations activate helixloop-helix family member B5 (Bhlhb5)-positive inhibitory interneurons. These interneurons exert their inhibitory effect on GPRP-positive neurons through releasing inhibitory neurotransmitters: dynorphin, glycine, and gamma-amino butyric acid.…”

Section: Itch Processing In the Spinal Cordmentioning

confidence: 99%

Itch: From mechanism to (novel) therapeutic approaches

Yosipovitch

Rosen

Hashimoto

2018

Journal of Allergy and Clinical Immunology

246

307

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Itch is a common sensory experience that is prevalent in patients with inflammatory skin diseases, as well as in those with systemic and neuropathic conditions. In patients with these conditions, itch is often severe and significantly affects quality of life. Itch is encoded by 2 major neuronal pathways: histaminergic (in acute itch) and nonhistaminergic (in chronic itch). In the majority of cases, crosstalk existing between keratinocytes, the immune system, and nonhistaminergic sensory nerves is responsible for the pathophysiology of chronic itch. This review provides an overview of the current understanding of the molecular, neural, and immune mechanisms of itch: beginning in the skin, proceeding to the spinal cord, and eventually ascending to the brain, where itch is processed. A growing understanding of the mechanisms of chronic itch is expanding, as is our pipeline of more targeted topical and systemic therapies. Our therapeutic armamentarium for treating chronic itch has expanded in the last 5 years, with developments of topical and systemic treatments targeting the neural and immune systems.

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“…TRP cation channel subfamily M member 8 (TRPM8) channels are located on the end of epidermal nerve fibres and Merkel cells (107). TRPM8 channels are cold-gated ion channels that inhibit both the histaminergic and non-histaminergic itch sensory pathways when activated (108). A novel TRPM8 cooling compound has been developed that, when incorporated into a lotion, signi- Defective corneocyte envelope formation (91), and defective lipid content and metabolism (92) Increased transepidermal water loss and abnormal permeability (93) Psoriasis Abnormal epidermal differentiation and immunological deviations, e.g.…”

Section: Novel Targets For Topical Treatments and Ingredientsmentioning

confidence: 99%

Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions

Yosipovitch¹,

Miséry²,

Proksch³

et al. 2019

Acta Derm Venereol

112

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Itch is a common symptom of many skin barrier-related dermatoses and can severely impact quality of life. However, there are a limited number of effective anti-itch topical therapies currently available and several unmet needs not addressed by current itch management strategies. As our knowledge of the mechanisms underlying itch has improved, several novel therapies have recently emerged that can be incorporated into existing regimens to enhance itch therapy and management. Here, we summarise research and current opinion on available topical therapies and give recommendations for the optimal management of itch. Barrier damage, dry skin and itch are intricately linked and form the basis of many common skin diseases. Damage from environmental insults, or genetic or inflammatory causes, can impair the skin barrier, resulting in an increase in transepidermal water loss and activation of itch-associated nerve fibres. The itch-scratch cycle can perpetuate skin barrier damage and itch. Topical therapeutic strategies are utilised to overcome dry skin and itch, primarily in the form of emollients. Recent advances in our understanding of the mechanisms underlying itch have enabled the development of new topical therapies, which may be incorporated into existing treatment regimes. Ultimately, treatment of dry skin and itch must be highly tailored to the individual according to their needs.

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Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons

Cited by 65 publications

References 46 publications

Tetrodotoxin-sensitive sodium channels mediate action potential firing and excitability in menthol-sensitive Vglut3-lineage sensory neurons

Tetrodotoxin-sensitive sodium channels mediate action potential firing and excitability in menthol-sensitive Vglut3-lineage sensory neurons

Itch: From mechanism to (novel) therapeutic approaches

Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions

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