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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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Significance of S1P1-mediated heat hypersensitivity.(A) Injection of the S1P1-selective agonist SEW2871 induced a significant reduction of PWL in C57BL/6J mice (100 µM, 5 µl, n = 8, *p<0.05, **p<0.01; ANOVA). (B) Conditioning stimulation of DRG neurons with the S1P1 agonist SEW2871 (1 µM) induced an increase in Icaps in an isolated DRG neuron. (C) SEW2871 (1 µM) significantly elevated average responses to consecutive capsaicin stimuli (1 to 4, 3 s at 120 s intervals) by a factor of 2.47±0.41 compared with control peak amplitudes (n = 6, *p<0.05; Wilcoxon matched pairs test). (D) Dose-response relationship of SEW2871 sensitization of Icaps. The ED50 was 0.56 µM and the maximum effect was observed with 1 µM SEW2871, the same concentration that gave the highest responses for S1P.
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pone-0017268-g004: Significance of S1P1-mediated heat hypersensitivity.(A) Injection of the S1P1-selective agonist SEW2871 induced a significant reduction of PWL in C57BL/6J mice (100 µM, 5 µl, n = 8, *p<0.05, **p<0.01; ANOVA). (B) Conditioning stimulation of DRG neurons with the S1P1 agonist SEW2871 (1 µM) induced an increase in Icaps in an isolated DRG neuron. (C) SEW2871 (1 µM) significantly elevated average responses to consecutive capsaicin stimuli (1 to 4, 3 s at 120 s intervals) by a factor of 2.47±0.41 compared with control peak amplitudes (n = 6, *p<0.05; Wilcoxon matched pairs test). (D) Dose-response relationship of SEW2871 sensitization of Icaps. The ED50 was 0.56 µM and the maximum effect was observed with 1 µM SEW2871, the same concentration that gave the highest responses for S1P.

Mentions: SEW2871 was developed as a selective agonist of S1P1 receptors [40]. Intracutaneous administration of SEW2871 (5 µl, 100 µM) induced heat hypersensitivity in vivo, and mean paw withdrawal latencies to noxious heat stimulation dropped significantly to a degree similar to that obtained for S1P injection (n = 8, p<0.05; ANOVA; Fig. 4A). The time course of SEW2871-induced heat hypersensitivity was similar to that of S1P and recovered slowly two hours after injection. In acutely isolated neurons, Icaps was potentiated by SEW2871 with a time course and half maximal concentration similar to those seen in response to S1P (Fig. 3B–D). SEW2871 facilitated Icaps, and peak current amplitudes transiently increased in a dose-dependent manner with the maximum effect occurring at 1 µM (2.46±0.50 fold, p<0.05, n = 6; Wilcoxon matched pairs test; Fig. 4D). These similarities support our hypothesis that nociceptor sensitization predominantly occurred through activation of the S1P1 receptor.


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)

Significance of S1P1-mediated heat hypersensitivity.(A) Injection of the S1P1-selective agonist SEW2871 induced a significant reduction of PWL in C57BL/6J mice (100 µM, 5 µl, n = 8, *p<0.05, **p<0.01; ANOVA). (B) Conditioning stimulation of DRG neurons with the S1P1 agonist SEW2871 (1 µM) induced an increase in Icaps in an isolated DRG neuron. (C) SEW2871 (1 µM) significantly elevated average responses to consecutive capsaicin stimuli (1 to 4, 3 s at 120 s intervals) by a factor of 2.47±0.41 compared with control peak amplitudes (n = 6, *p<0.05; Wilcoxon matched pairs test). (D) Dose-response relationship of SEW2871 sensitization of Icaps. The ED50 was 0.56 µM and the maximum effect was observed with 1 µM SEW2871, the same concentration that gave the highest responses for S1P.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017268-g004: Significance of S1P1-mediated heat hypersensitivity.(A) Injection of the S1P1-selective agonist SEW2871 induced a significant reduction of PWL in C57BL/6J mice (100 µM, 5 µl, n = 8, *p<0.05, **p<0.01; ANOVA). (B) Conditioning stimulation of DRG neurons with the S1P1 agonist SEW2871 (1 µM) induced an increase in Icaps in an isolated DRG neuron. (C) SEW2871 (1 µM) significantly elevated average responses to consecutive capsaicin stimuli (1 to 4, 3 s at 120 s intervals) by a factor of 2.47±0.41 compared with control peak amplitudes (n = 6, *p<0.05; Wilcoxon matched pairs test). (D) Dose-response relationship of SEW2871 sensitization of Icaps. The ED50 was 0.56 µM and the maximum effect was observed with 1 µM SEW2871, the same concentration that gave the highest responses for S1P.
Mentions: SEW2871 was developed as a selective agonist of S1P1 receptors [40]. Intracutaneous administration of SEW2871 (5 µl, 100 µM) induced heat hypersensitivity in vivo, and mean paw withdrawal latencies to noxious heat stimulation dropped significantly to a degree similar to that obtained for S1P injection (n = 8, p<0.05; ANOVA; Fig. 4A). The time course of SEW2871-induced heat hypersensitivity was similar to that of S1P and recovered slowly two hours after injection. In acutely isolated neurons, Icaps was potentiated by SEW2871 with a time course and half maximal concentration similar to those seen in response to S1P (Fig. 3B–D). SEW2871 facilitated Icaps, and peak current amplitudes transiently increased in a dose-dependent manner with the maximum effect occurring at 1 µM (2.46±0.50 fold, p<0.05, n = 6; Wilcoxon matched pairs test; Fig. 4D). These similarities support our hypothesis that nociceptor sensitization predominantly occurred through activation of the S1P1 receptor.

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