Endothelin-1 induces itch and pain in the mouse cheek model

Gomes, Lenyta Oliveira; Hara, Daniela Balz; Rae, Giles A.

doi:10.1016/j.lfs.2012.03.020

Cited by 43 publications

(32 citation statements)

References 30 publications

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“…51, 52). Gomes et al (51) reported that ET-1 also acts as a nociceptive agonist, thus we took advantage of the cheek model to distinguish between ET-1-induced scratching and pain behavior (53). In our experimental setting, ET-1 induced a concentration-dependent scratching response (from 1 pmol to 1 nmol/site, Supplemental Figure 2).…”

Section: Figurementioning

confidence: 99%

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

et al. 2014

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In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.

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Section: Figurementioning

confidence: 99%

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

et al. 2014

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“…In mice, intradermal (i.d.) injection of ET-1 produces a robust scratching response in numerous studies [2, 94–97]. ET-1-induced itching is mediated mainly by the endothelin receptor type A (ETA) as the ETA antagonist BQ123, but not the ETB antagonist BQ788, significantly reduces the scratching evoked by ET-1 [95].…”

Section: The Molecular Basis Of Pain and Itchmentioning

confidence: 99%

“…ET-1 evokes not only scratching (itch sensation) but also wiping (pain sensation) towards the injection site in the mouse cheek injection model. The ETA antagonist BQ123 but not the ETB antagonist BQ788 suppresses both ET-1-evoked scratching and wiping, suggesting that ETA also mediates ET-1-induced pain responses [97]. On the other hand, BQ788 enhances ET-1-induced pain-like behavior and local injection of a selective ETB agonist IRL-1620 inhibits the ET-1-induced pain responses in rats, suggesting that activation of ETB produces analgesic effects [103].…”

Section: The Molecular Basis Of Pain and Itchmentioning

confidence: 99%

Molecular and cellular mechanisms that initiate pain and itch

Luo

Feng

Liu

et al. 2015

Cell. Mol. Life Sci.

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Somatosensory neurons mediate our sense of touch. They are critically involved in transducing pain and itch sensations under physiological and pathological conditions, along with other skin resident cells. Tissue damage and inflammation can produce a localized or systemic sensitization of our senses of pain and itch, which can facilitate our detection of threats in the environment. Although acute pain and itch protect us from further damage, persistent pain and itch are debilitating. Recent exciting discoveries have significantly advanced our knowledge of the roles of membrane-bound G protein-coupled receptors and ion channels in the encoding of information leading to pain and itch sensations. This review focuses on molecular and cellular events that are important in early stages of the biological processing that culminates in our senses of pain and itch.

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“…Another peripheral mediator, endothelin-1 (ET-1), was found to induce both itch and pain behaviors in mice, as distinguished by the cheek injection model 13 . ET-1 iontophoresis also induced itch in human subjects, and ET-1 and its downstream mediators were upregulated in patients with prurigo nodularis and chronic itch 14 .…”

Section: Peripheral Mediators Of Itchmentioning

confidence: 99%

Advances in understanding itching and scratching: a new era of targeted treatments

2016

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Chronic itch is a significant health burden with few effective treatments. As such, itch researchers seek to understand the mechanisms behind itch and to find potential targets for treatment. The field of itch research is dynamic, and many advances have been made so far this decade. In particular, major steps forward include the identification of new peripheral and central itch mediators and modulators, the discovery of greater roles for immune cells and glia in itch transmission, and a focus on the brain processing of itching and scratching. Finally, several new therapeutic interventions for itch have shown success in clinical trials.

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Endothelin-1 induces itch and pain in the mouse cheek model

Cited by 43 publications

References 30 publications

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

Molecular and cellular mechanisms that initiate pain and itch

Advances in understanding itching and scratching: a new era of targeted treatments

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