Atopic dermatitis and inflammatory skin disease
Substance P activates Mas-related G protein–coupled receptors to induce itch

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Background

Substance P (SP) is linked to itch and inflammation through activation of receptors on mast cells and sensory neurons. There is increasing evidence that SP functions through Mas-related G protein–coupled receptors (Mrgprs) in addition to its conventional receptor, neurokinin-1.

Objective

Because Mrgprs mediate some aspects of inflammation that had been considered mediated by neurokinin-1 receptor (NK-1R), we sought to determine whether itch induced by SP can also be mediated by Mrgprs.

Methods

Genetic and pharmacologic approaches were used to evaluate the contribution of Mrgprs to SP-induced scratching behavior and activation of cultured dorsal root ganglion neurons from mice.

Results

SP-induced scratching behavior and activation of cultured dorsal root ganglion neurons was dependent on Mrgprs rather than NK-1R.

Conclusion

We deduce that SP activates MrgprA1 on sensory neurons rather than NK-1R to induce itch.

Section snippets

Peptides and chemicals

SP was obtained from GenScript (Piscataway, NJ) and dissolved in 1× PBS. The NK-1R antagonist L733060 and the dual NK-1R/Mrgprs antagonist QWF (Boc-Gln-D-Trp[formyl]-Phe benzyl ester trifluoroacetate) were obtained from Sigma (St Louis, Mo). QWF and L733060 were dissolved in dimethyl sulfoxide (DMSO; Sigma) at 10 mmol/L and diluted in PBS for use at concentrations of 500 μmol/L or less. In the nociceptive studies with capsaicin, in which QWF was diluted in DMSO, the final concentration of DMSO

SP-induced itch behavior is dependent on Mrgprs

We first investigated whether Mrgprs played a role in SP-induced scratching behavior. We used the mouse cheek model17 to evaluate the pruritogenic effect of SP in Mrgpr cluster Δ−/− mice in which 12 Mrgprs had been knocked out.10 SP-induced itch was significantly decreased in these animals compared with that seen in wild-type mice (Fig 1, A). This result is consistent with previous studies suggesting a role for DRG neurons in addition to mast cells in patients with SP-induced itch.6, 14 To

Discussion

The limited efficacy of antihistamines in most pruritic conditions20, 21 highlights the importance of histamine-independent mechanisms of itch. Mrgprs are among the most important mediators of histamine-independent itch.22 This article further addresses the role of Mrgprs in itch by indicating a specific role for MrgprA1 in SP-induced itch in mice. SP has been implicated in various cutaneous and systemic pruritic disorders, such as atopic dermatitis23, 24 and cholestasis.25 We have previously

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    E.A. is the recipient of a grant from the National Eczema Association. S.T. holds postdoctoral fellowships from the Canadian Institute of Health and Research. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases R01AR057744 and R21AR067399 (to E.A.L.) and the National Institute of Child Health (HD018655) and Human Development and National Institute of Neurological Disorders and Stroke (R37NS039518; to C.J.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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