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Pirt, a TRPV1 modulator, is required for histamine-dependent and -independent itch.

Patel KN, Liu Q, Meeker S, Undem BJ, Dong X - PLoS ONE (2011)

Bottom Line: Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood.Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation.Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood. Recent work has begun to identify genes that contribute to detecting itch at the molecular level. Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation. Pirt(-/-) mice exhibit deficits in cellular and behavioral responses to various itch-inducing compounds, or pruritogens. Pirt contributes to both histaminergic and nonhistaminergic itch and, crucially, is involved in forms of itch that are both TRPV1-dependent and -independent. Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways.

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Pirt contributes to histaminergic itch.(A) The time course shows scratching bouts, presented as mean ± SEM, in response to histamine injection (10 µmol) over a 30 min period divided into 5 min intervals. (B) Total bouts of scratching over the 30 min observation period show Pirt−/− mice (n = 7) have decreased behavioral responses to histamine compared to WT mice (n = 8). (C) Ca2+ imaging shows fewer DRG neurons from Pirt KO mice respond to histamine (50 µM) than WT mice (n = 5 per genotype). (D, E) Pirt mutant mice (n = 10) also scratch less upon injection of the histamine H1 receptor-selective agonist HTMT (0.1 µmol) than WT (n = 9). * p<0.05, ** p<0.001, *** p<0.0001; two-tailed unpaired t-test.
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pone-0020559-g001: Pirt contributes to histaminergic itch.(A) The time course shows scratching bouts, presented as mean ± SEM, in response to histamine injection (10 µmol) over a 30 min period divided into 5 min intervals. (B) Total bouts of scratching over the 30 min observation period show Pirt−/− mice (n = 7) have decreased behavioral responses to histamine compared to WT mice (n = 8). (C) Ca2+ imaging shows fewer DRG neurons from Pirt KO mice respond to histamine (50 µM) than WT mice (n = 5 per genotype). (D, E) Pirt mutant mice (n = 10) also scratch less upon injection of the histamine H1 receptor-selective agonist HTMT (0.1 µmol) than WT (n = 9). * p<0.05, ** p<0.001, *** p<0.0001; two-tailed unpaired t-test.

Mentions: We used a well-established assay to measure behavioral responses of mice to various itch-inducing compounds [9]. Histamine is known to generate a form of itch that is TRPV1-dependent [6], [7], suggesting a role for Pirt in this process. As predicted, histamine produces itch in wild type mice (108 bouts of scratching) that is severely reduced in Pirt−/− littermates (12 bouts, Fig. 1A, B). In addition to producing a behavioral scratch response, many pruritogens can directly activate DRG neurons in vitro to generate intracellular calcium and/or electrophysiological responses. Histamine has been shown to directly activate DRG neurons and this response is decreased in the presence of a TRPV1 antagonist [6], [10]. The percentage of neurons responding to histamine is significantly reduced in DRG cultures from Pirt−/− mice (5.3%) compared to wild type controls (9.8%, Fig. 1C). Histamine trifluoromethyl toluidide (HTMT), an agonist selective for the histamine H1 receptor [11], can also induce scratching, and this is strongly attenuated in Pirt−/− mice (91 bouts in WT vs. 27 bouts in Pirt KO, Fig. 1D, E). These data suggest a contribution of Pirt to histaminergic itch signaling through the H1 receptor, although another related protein, the histamine H4 receptor, may also be involved in histamine-dependent itch [12], [13].


Pirt, a TRPV1 modulator, is required for histamine-dependent and -independent itch.

Patel KN, Liu Q, Meeker S, Undem BJ, Dong X - PLoS ONE (2011)

Pirt contributes to histaminergic itch.(A) The time course shows scratching bouts, presented as mean ± SEM, in response to histamine injection (10 µmol) over a 30 min period divided into 5 min intervals. (B) Total bouts of scratching over the 30 min observation period show Pirt−/− mice (n = 7) have decreased behavioral responses to histamine compared to WT mice (n = 8). (C) Ca2+ imaging shows fewer DRG neurons from Pirt KO mice respond to histamine (50 µM) than WT mice (n = 5 per genotype). (D, E) Pirt mutant mice (n = 10) also scratch less upon injection of the histamine H1 receptor-selective agonist HTMT (0.1 µmol) than WT (n = 9). * p<0.05, ** p<0.001, *** p<0.0001; two-tailed unpaired t-test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105090&req=5

pone-0020559-g001: Pirt contributes to histaminergic itch.(A) The time course shows scratching bouts, presented as mean ± SEM, in response to histamine injection (10 µmol) over a 30 min period divided into 5 min intervals. (B) Total bouts of scratching over the 30 min observation period show Pirt−/− mice (n = 7) have decreased behavioral responses to histamine compared to WT mice (n = 8). (C) Ca2+ imaging shows fewer DRG neurons from Pirt KO mice respond to histamine (50 µM) than WT mice (n = 5 per genotype). (D, E) Pirt mutant mice (n = 10) also scratch less upon injection of the histamine H1 receptor-selective agonist HTMT (0.1 µmol) than WT (n = 9). * p<0.05, ** p<0.001, *** p<0.0001; two-tailed unpaired t-test.
Mentions: We used a well-established assay to measure behavioral responses of mice to various itch-inducing compounds [9]. Histamine is known to generate a form of itch that is TRPV1-dependent [6], [7], suggesting a role for Pirt in this process. As predicted, histamine produces itch in wild type mice (108 bouts of scratching) that is severely reduced in Pirt−/− littermates (12 bouts, Fig. 1A, B). In addition to producing a behavioral scratch response, many pruritogens can directly activate DRG neurons in vitro to generate intracellular calcium and/or electrophysiological responses. Histamine has been shown to directly activate DRG neurons and this response is decreased in the presence of a TRPV1 antagonist [6], [10]. The percentage of neurons responding to histamine is significantly reduced in DRG cultures from Pirt−/− mice (5.3%) compared to wild type controls (9.8%, Fig. 1C). Histamine trifluoromethyl toluidide (HTMT), an agonist selective for the histamine H1 receptor [11], can also induce scratching, and this is strongly attenuated in Pirt−/− mice (91 bouts in WT vs. 27 bouts in Pirt KO, Fig. 1D, E). These data suggest a contribution of Pirt to histaminergic itch signaling through the H1 receptor, although another related protein, the histamine H4 receptor, may also be involved in histamine-dependent itch [12], [13].

Bottom Line: Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood.Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation.Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood. Recent work has begun to identify genes that contribute to detecting itch at the molecular level. Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation. Pirt(-/-) mice exhibit deficits in cellular and behavioral responses to various itch-inducing compounds, or pruritogens. Pirt contributes to both histaminergic and nonhistaminergic itch and, crucially, is involved in forms of itch that are both TRPV1-dependent and -independent. Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways.

Show MeSH
Related in: MedlinePlus