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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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Reduced thermal hypersensitivity in S1P1−/−mice.(A) Injection of the S1P1 agonist SEW2871 induced a significant transient decrease in paw withdrawal latencies in S1P1fl/fl (n = 9) which was significantly less pronounced than in SNS-S1P1−/− mice (n = 10, *p<0.05; ANOVA). (B, C) While only a minor reduction of paw withdrawal latencies was observed in both mouse strains with local low dose S1P injection, we observed a significant decrease in paw withdrawal latencies in S1P1fl/fl mice (n = 7) which was similar to wt. In SNS-S1P1−/− mice the degree of hypersensitivity was significantly ameliorated in comparison to S1P1fl/fl mice (n = 9, *p<0.05, ** p<0.01; ANOVA). (D) CFA (20 µl) injection into the plantar hindpaw induced a pronounced decrease of PWL which was significantly attenuated in S1P1-Cre mice (p<0.05, n = 4; ANOVA). (E) Paw swelling was similar in SNS-S1P1−/− and S1P1fl/fl mice (n = 4).
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pone-0017268-g006: Reduced thermal hypersensitivity in S1P1−/−mice.(A) Injection of the S1P1 agonist SEW2871 induced a significant transient decrease in paw withdrawal latencies in S1P1fl/fl (n = 9) which was significantly less pronounced than in SNS-S1P1−/− mice (n = 10, *p<0.05; ANOVA). (B, C) While only a minor reduction of paw withdrawal latencies was observed in both mouse strains with local low dose S1P injection, we observed a significant decrease in paw withdrawal latencies in S1P1fl/fl mice (n = 7) which was similar to wt. In SNS-S1P1−/− mice the degree of hypersensitivity was significantly ameliorated in comparison to S1P1fl/fl mice (n = 9, *p<0.05, ** p<0.01; ANOVA). (D) CFA (20 µl) injection into the plantar hindpaw induced a pronounced decrease of PWL which was significantly attenuated in S1P1-Cre mice (p<0.05, n = 4; ANOVA). (E) Paw swelling was similar in SNS-S1P1−/− and S1P1fl/fl mice (n = 4).

Mentions: SNS-S1P1−/− mice were viable and did not show any obvious deficits in spontaneous behavior, motor capabilities or breeding. Baseline mechanical and thermal thresholds of cutaneous sensory neurons were similar to S1P1fl/fl littermates. In S1P1fl/fl mice, intracutaneous injection of the S1P1 receptor agonist SEW2871 resulted in a transient and significant drop in paw withdrawal latencies which fully recovered after two hours (Fig. 6A). In SNS-S1P1−/− mice, the change in heat sensitivity was equal to vehicle injection. Lower doses of S1P itself induced a short hypersensitivity that was similar in S1P1fl/fl and SNS-S1P1−/− mice (Fig. 6B). At higher doses, S1P induced similar reductions in withdrawal latencies in S1P1fl/fl and C56BL/6J wt mice, however, the decrease in paw withdrawal latency was significantly smaller in SNS-S1P1−/− (Fig. 6C). Moreover, in SNS-S1P1−/− mice the decrease of paw withdrawal latency after CFA-induced inflammation was significantly reduced in comparison to S1P1fl/fl (5.8±0.6 s vs. 3.3±0.5 s, 6 h after CFA injection; n = 8; ANOVA repeated measures and Tukey post hoc test, genotype: F(1,79)  = 24.9; p<0.001, time points: F(4,79)  = 39.7; p<0.001; genotype × time points: F(4,79)  = 2.82; p = 0.033; Fig. 6D). The degree of inflammation (shown as ratiopaw swelling; Fig. 6E) was similar in both groups. The degree of mechanical hypersensitivity after S1P injection was not significantly different from controls in SNS-S1P1−/− mice (9.5±1.1 mN before vs. 3.7±0.8 mN, 6 h after CFA injection; n = 7; ANOVA). Based on the evidence we found, we propose that S1P/S1P1 receptor signaling in nociceptive primary afferents could be relevant for inflammatory pain.


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)

Reduced thermal hypersensitivity in S1P1−/−mice.(A) Injection of the S1P1 agonist SEW2871 induced a significant transient decrease in paw withdrawal latencies in S1P1fl/fl (n = 9) which was significantly less pronounced than in SNS-S1P1−/− mice (n = 10, *p<0.05; ANOVA). (B, C) While only a minor reduction of paw withdrawal latencies was observed in both mouse strains with local low dose S1P injection, we observed a significant decrease in paw withdrawal latencies in S1P1fl/fl mice (n = 7) which was similar to wt. In SNS-S1P1−/− mice the degree of hypersensitivity was significantly ameliorated in comparison to S1P1fl/fl mice (n = 9, *p<0.05, ** p<0.01; ANOVA). (D) CFA (20 µl) injection into the plantar hindpaw induced a pronounced decrease of PWL which was significantly attenuated in S1P1-Cre mice (p<0.05, n = 4; ANOVA). (E) Paw swelling was similar in SNS-S1P1−/− and S1P1fl/fl mice (n = 4).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3040773&req=5

pone-0017268-g006: Reduced thermal hypersensitivity in S1P1−/−mice.(A) Injection of the S1P1 agonist SEW2871 induced a significant transient decrease in paw withdrawal latencies in S1P1fl/fl (n = 9) which was significantly less pronounced than in SNS-S1P1−/− mice (n = 10, *p<0.05; ANOVA). (B, C) While only a minor reduction of paw withdrawal latencies was observed in both mouse strains with local low dose S1P injection, we observed a significant decrease in paw withdrawal latencies in S1P1fl/fl mice (n = 7) which was similar to wt. In SNS-S1P1−/− mice the degree of hypersensitivity was significantly ameliorated in comparison to S1P1fl/fl mice (n = 9, *p<0.05, ** p<0.01; ANOVA). (D) CFA (20 µl) injection into the plantar hindpaw induced a pronounced decrease of PWL which was significantly attenuated in S1P1-Cre mice (p<0.05, n = 4; ANOVA). (E) Paw swelling was similar in SNS-S1P1−/− and S1P1fl/fl mice (n = 4).
Mentions: SNS-S1P1−/− mice were viable and did not show any obvious deficits in spontaneous behavior, motor capabilities or breeding. Baseline mechanical and thermal thresholds of cutaneous sensory neurons were similar to S1P1fl/fl littermates. In S1P1fl/fl mice, intracutaneous injection of the S1P1 receptor agonist SEW2871 resulted in a transient and significant drop in paw withdrawal latencies which fully recovered after two hours (Fig. 6A). In SNS-S1P1−/− mice, the change in heat sensitivity was equal to vehicle injection. Lower doses of S1P itself induced a short hypersensitivity that was similar in S1P1fl/fl and SNS-S1P1−/− mice (Fig. 6B). At higher doses, S1P induced similar reductions in withdrawal latencies in S1P1fl/fl and C56BL/6J wt mice, however, the decrease in paw withdrawal latency was significantly smaller in SNS-S1P1−/− (Fig. 6C). Moreover, in SNS-S1P1−/− mice the decrease of paw withdrawal latency after CFA-induced inflammation was significantly reduced in comparison to S1P1fl/fl (5.8±0.6 s vs. 3.3±0.5 s, 6 h after CFA injection; n = 8; ANOVA repeated measures and Tukey post hoc test, genotype: F(1,79)  = 24.9; p<0.001, time points: F(4,79)  = 39.7; p<0.001; genotype × time points: F(4,79)  = 2.82; p = 0.033; Fig. 6D). The degree of inflammation (shown as ratiopaw swelling; Fig. 6E) was similar in both groups. The degree of mechanical hypersensitivity after S1P injection was not significantly different from controls in SNS-S1P1−/− mice (9.5±1.1 mN before vs. 3.7±0.8 mN, 6 h after CFA injection; n = 7; ANOVA). Based on the evidence we found, we propose that S1P/S1P1 receptor signaling in nociceptive primary afferents could be relevant for inflammatory pain.

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