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Genetic evidence for involvement of neuronally expressed S1P₁ receptor in nociceptor sensitization and inflammatory pain.

Mair N, Benetti C, Andratsch M, Leitner MG, Constantin CE, Camprubí-Robles M, Quarta S, Biasio W, Kuner R, Gibbins IL, Kress M, Haberberger RV - PLoS ONE (2011)

Bottom Line: Immune cells, epithelia and blood cells generate high levels of S1P in inflamed tissue.We found that the S1P₁ receptor for S1P is expressed in subpopulations of sensory neurons including nociceptors.Our data show that neuronally expressed S1P₁ receptors play a significant role in regulating nociceptor function and that S1P/S1P₁ signaling may be a key player in the onset of thermal hypersensitivity and hyperalgesia associated with inflammation.

View Article: PubMed Central - PubMed

Affiliation: Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Austria. norbert.mair@i-med.ac.at

ABSTRACT
Sphingosine-1-phosphate (S1P) is a key regulator of immune response. Immune cells, epithelia and blood cells generate high levels of S1P in inflamed tissue. However, it is not known if S1P acts on the endings of nociceptive neurons, thereby contributing to the generation of inflammatory pain. We found that the S1P₁ receptor for S1P is expressed in subpopulations of sensory neurons including nociceptors. Both S1P and agonists at the S1P₁ receptor induced hypersensitivity to noxious thermal stimulation in vitro and in vivo. S1P-induced hypersensitivity was strongly attenuated in mice lacking TRPV1 channels. S1P and inflammation-induced hypersensitivity was significantly reduced in mice with a conditional nociceptor-specific deletion of the S1P₁ receptor. Our data show that neuronally expressed S1P₁ receptors play a significant role in regulating nociceptor function and that S1P/S1P₁ signaling may be a key player in the onset of thermal hypersensitivity and hyperalgesia associated with inflammation.

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S1P-induced hypersensitivity largely depends on TRPV1 channels.(A) Currents elicited by the TRPV1 activator capsaicin (500 nM for 10 s, black boxes) were strongly facilitated after S1P (1 µM, 60 s, open box). (B) Average responses to repeated stimulation with 500 nM capsaicin before and after S1P (duration 3 s, interval 120 s). Icaps significantly increased by a factor of 3.1±0.74 after conditioning S1P application (n = 9, p<0.01; Wilcoxon matched pairs test) and fully recovered within 4 min. (C) Dose-response relationship for S1P-induced facilitation of Icaps. A maximum effect was observed at a S1P concentration of 1 µM with a half-effective dose ED50 of 0.55 µM. At concentrations exceeding 1 µM the sensitizing effect of S1P became less pronounced. (D) The S1P-induced reduction in paw withdrawal latencies was significantly attenuated but not fully abolished in TRPV1  mutant mice (filled squares) as compared to wt littermates (open squares, n = 0, *p<0.05, **p<0.01, *** p<0.001; ANOVA).
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pone-0017268-g002: S1P-induced hypersensitivity largely depends on TRPV1 channels.(A) Currents elicited by the TRPV1 activator capsaicin (500 nM for 10 s, black boxes) were strongly facilitated after S1P (1 µM, 60 s, open box). (B) Average responses to repeated stimulation with 500 nM capsaicin before and after S1P (duration 3 s, interval 120 s). Icaps significantly increased by a factor of 3.1±0.74 after conditioning S1P application (n = 9, p<0.01; Wilcoxon matched pairs test) and fully recovered within 4 min. (C) Dose-response relationship for S1P-induced facilitation of Icaps. A maximum effect was observed at a S1P concentration of 1 µM with a half-effective dose ED50 of 0.55 µM. At concentrations exceeding 1 µM the sensitizing effect of S1P became less pronounced. (D) The S1P-induced reduction in paw withdrawal latencies was significantly attenuated but not fully abolished in TRPV1 mutant mice (filled squares) as compared to wt littermates (open squares, n = 0, *p<0.05, **p<0.01, *** p<0.001; ANOVA).

Mentions: One important thermosensitive ion channel in nociceptive neurons is the capsaicin-activated transient receptor potential vanilloid receptor, TRPV1 [31]. We found that S1P augmented capsaicin-induced currents (Icaps) with a half maximal effective concentration of 0.55 µM under controlled single cell perfusion conditions (500 nM capsaicin; p<0.01; n = 7; Wilcoxon matched pairs test Fig. 2A, B). The maximum increase occurred at 1 µM S1P; lower and higher concentrations were less effective. S1P-induced heat hyperalgesia was significantly ameliorated, but not fully abolished, in TRPV1−/− mice compared with wt littermates (Fig. 2D).


Genetic evidence for involvement of neuronally expressed S1P₁ receptor in nociceptor sensitization and inflammatory pain.

Mair N, Benetti C, Andratsch M, Leitner MG, Constantin CE, Camprubí-Robles M, Quarta S, Biasio W, Kuner R, Gibbins IL, Kress M, Haberberger RV - PLoS ONE (2011)

S1P-induced hypersensitivity largely depends on TRPV1 channels.(A) Currents elicited by the TRPV1 activator capsaicin (500 nM for 10 s, black boxes) were strongly facilitated after S1P (1 µM, 60 s, open box). (B) Average responses to repeated stimulation with 500 nM capsaicin before and after S1P (duration 3 s, interval 120 s). Icaps significantly increased by a factor of 3.1±0.74 after conditioning S1P application (n = 9, p<0.01; Wilcoxon matched pairs test) and fully recovered within 4 min. (C) Dose-response relationship for S1P-induced facilitation of Icaps. A maximum effect was observed at a S1P concentration of 1 µM with a half-effective dose ED50 of 0.55 µM. At concentrations exceeding 1 µM the sensitizing effect of S1P became less pronounced. (D) The S1P-induced reduction in paw withdrawal latencies was significantly attenuated but not fully abolished in TRPV1  mutant mice (filled squares) as compared to wt littermates (open squares, n = 0, *p<0.05, **p<0.01, *** p<0.001; ANOVA).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040773&req=5

pone-0017268-g002: S1P-induced hypersensitivity largely depends on TRPV1 channels.(A) Currents elicited by the TRPV1 activator capsaicin (500 nM for 10 s, black boxes) were strongly facilitated after S1P (1 µM, 60 s, open box). (B) Average responses to repeated stimulation with 500 nM capsaicin before and after S1P (duration 3 s, interval 120 s). Icaps significantly increased by a factor of 3.1±0.74 after conditioning S1P application (n = 9, p<0.01; Wilcoxon matched pairs test) and fully recovered within 4 min. (C) Dose-response relationship for S1P-induced facilitation of Icaps. A maximum effect was observed at a S1P concentration of 1 µM with a half-effective dose ED50 of 0.55 µM. At concentrations exceeding 1 µM the sensitizing effect of S1P became less pronounced. (D) The S1P-induced reduction in paw withdrawal latencies was significantly attenuated but not fully abolished in TRPV1 mutant mice (filled squares) as compared to wt littermates (open squares, n = 0, *p<0.05, **p<0.01, *** p<0.001; ANOVA).
Mentions: One important thermosensitive ion channel in nociceptive neurons is the capsaicin-activated transient receptor potential vanilloid receptor, TRPV1 [31]. We found that S1P augmented capsaicin-induced currents (Icaps) with a half maximal effective concentration of 0.55 µM under controlled single cell perfusion conditions (500 nM capsaicin; p<0.01; n = 7; Wilcoxon matched pairs test Fig. 2A, B). The maximum increase occurred at 1 µM S1P; lower and higher concentrations were less effective. S1P-induced heat hyperalgesia was significantly ameliorated, but not fully abolished, in TRPV1−/− mice compared with wt littermates (Fig. 2D).

Bottom Line: Immune cells, epithelia and blood cells generate high levels of S1P in inflamed tissue.We found that the S1P₁ receptor for S1P is expressed in subpopulations of sensory neurons including nociceptors.Our data show that neuronally expressed S1P₁ receptors play a significant role in regulating nociceptor function and that S1P/S1P₁ signaling may be a key player in the onset of thermal hypersensitivity and hyperalgesia associated with inflammation.

View Article: PubMed Central - PubMed

Affiliation: Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Austria. norbert.mair@i-med.ac.at

ABSTRACT
Sphingosine-1-phosphate (S1P) is a key regulator of immune response. Immune cells, epithelia and blood cells generate high levels of S1P in inflamed tissue. However, it is not known if S1P acts on the endings of nociceptive neurons, thereby contributing to the generation of inflammatory pain. We found that the S1P₁ receptor for S1P is expressed in subpopulations of sensory neurons including nociceptors. Both S1P and agonists at the S1P₁ receptor induced hypersensitivity to noxious thermal stimulation in vitro and in vivo. S1P-induced hypersensitivity was strongly attenuated in mice lacking TRPV1 channels. S1P and inflammation-induced hypersensitivity was significantly reduced in mice with a conditional nociceptor-specific deletion of the S1P₁ receptor. Our data show that neuronally expressed S1P₁ receptors play a significant role in regulating nociceptor function and that S1P/S1P₁ signaling may be a key player in the onset of thermal hypersensitivity and hyperalgesia associated with inflammation.

Show MeSH
Related in: MedlinePlus