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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 sensitization of heat pain behavior, nociceptor neuron discharge in vitro and heat-activated ionic currents.(A) Injection of S1P into the paw skin (5 µl of a 100 µM S1P solution in PBS) but not vehicle (n = 10, n.s.) induced a significant transient drop in paw withdrawal latencies (PWL) in response to heat stimulation from 10.15±0.63 to 3.62±0.24 s (n = 10, *p<0.05; ANOVA). Heat sensitization fully recovered to baseline within three hours. (B) Discharge activity of single primary nociceptive neurons in vitro significantly increased from 2.03±0.39 before (black columns) to 3.21±0.50 Imp/s (grey columns) after the receptive fields of the fibers were exposed to 1 µM S1P for 5 min (n = 11, p<0.05; Wilcoxon matched pairs test). (C) After conditioning stimulation with S1P, the heat-induced current of a dorsal root ganglion neuron exhibited increased peak amplitudes and was activated at a lower temperature compared with control. (D) Temperature-current plots of four neurons stimulated with a ramp-shaped heat stimulus with a linear rise of temperature from room temperature to 50°C before (open circles) and after conditioning stimulation with S1P (filled circles, threshold temperature).
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pone-0017268-g001: S1P-induced sensitization of heat pain behavior, nociceptor neuron discharge in vitro and heat-activated ionic currents.(A) Injection of S1P into the paw skin (5 µl of a 100 µM S1P solution in PBS) but not vehicle (n = 10, n.s.) induced a significant transient drop in paw withdrawal latencies (PWL) in response to heat stimulation from 10.15±0.63 to 3.62±0.24 s (n = 10, *p<0.05; ANOVA). Heat sensitization fully recovered to baseline within three hours. (B) Discharge activity of single primary nociceptive neurons in vitro significantly increased from 2.03±0.39 before (black columns) to 3.21±0.50 Imp/s (grey columns) after the receptive fields of the fibers were exposed to 1 µM S1P for 5 min (n = 11, p<0.05; Wilcoxon matched pairs test). (C) After conditioning stimulation with S1P, the heat-induced current of a dorsal root ganglion neuron exhibited increased peak amplitudes and was activated at a lower temperature compared with control. (D) Temperature-current plots of four neurons stimulated with a ramp-shaped heat stimulus with a linear rise of temperature from room temperature to 50°C before (open circles) and after conditioning stimulation with S1P (filled circles, threshold temperature).

Mentions: The latency of the withdrawal reaction in response to radiant heat is a reliable parameter to monitor changes in sensitivity to painful heat stimuli in rodents [30]. Heat withdrawal latencies were determined in wt C57BL/6J mice that received intracutaneous injections of S1P (5 µl, 100 µM) in phosphate-buffered saline or vehicle only. Within fifteen minutes after injection of S1P but not vehicle, mean withdrawal latencies decreased significantly (p<0.05; Mann-Whitney U-test; Fig. 1A). Hypersensitivity to heat stimulation was maintained for more than two hours; after three hours, paw withdrawal latencies were no longer significantly different from vehicle-injected sites.


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 sensitization of heat pain behavior, nociceptor neuron discharge in vitro and heat-activated ionic currents.(A) Injection of S1P into the paw skin (5 µl of a 100 µM S1P solution in PBS) but not vehicle (n = 10, n.s.) induced a significant transient drop in paw withdrawal latencies (PWL) in response to heat stimulation from 10.15±0.63 to 3.62±0.24 s (n = 10, *p<0.05; ANOVA). Heat sensitization fully recovered to baseline within three hours. (B) Discharge activity of single primary nociceptive neurons in vitro significantly increased from 2.03±0.39 before (black columns) to 3.21±0.50 Imp/s (grey columns) after the receptive fields of the fibers were exposed to 1 µM S1P for 5 min (n = 11, p<0.05; Wilcoxon matched pairs test). (C) After conditioning stimulation with S1P, the heat-induced current of a dorsal root ganglion neuron exhibited increased peak amplitudes and was activated at a lower temperature compared with control. (D) Temperature-current plots of four neurons stimulated with a ramp-shaped heat stimulus with a linear rise of temperature from room temperature to 50°C before (open circles) and after conditioning stimulation with S1P (filled circles, threshold temperature).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017268-g001: S1P-induced sensitization of heat pain behavior, nociceptor neuron discharge in vitro and heat-activated ionic currents.(A) Injection of S1P into the paw skin (5 µl of a 100 µM S1P solution in PBS) but not vehicle (n = 10, n.s.) induced a significant transient drop in paw withdrawal latencies (PWL) in response to heat stimulation from 10.15±0.63 to 3.62±0.24 s (n = 10, *p<0.05; ANOVA). Heat sensitization fully recovered to baseline within three hours. (B) Discharge activity of single primary nociceptive neurons in vitro significantly increased from 2.03±0.39 before (black columns) to 3.21±0.50 Imp/s (grey columns) after the receptive fields of the fibers were exposed to 1 µM S1P for 5 min (n = 11, p<0.05; Wilcoxon matched pairs test). (C) After conditioning stimulation with S1P, the heat-induced current of a dorsal root ganglion neuron exhibited increased peak amplitudes and was activated at a lower temperature compared with control. (D) Temperature-current plots of four neurons stimulated with a ramp-shaped heat stimulus with a linear rise of temperature from room temperature to 50°C before (open circles) and after conditioning stimulation with S1P (filled circles, threshold temperature).
Mentions: The latency of the withdrawal reaction in response to radiant heat is a reliable parameter to monitor changes in sensitivity to painful heat stimuli in rodents [30]. Heat withdrawal latencies were determined in wt C57BL/6J mice that received intracutaneous injections of S1P (5 µl, 100 µM) in phosphate-buffered saline or vehicle only. Within fifteen minutes after injection of S1P but not vehicle, mean withdrawal latencies decreased significantly (p<0.05; Mann-Whitney U-test; Fig. 1A). Hypersensitivity to heat stimulation was maintained for more than two hours; after three hours, paw withdrawal latencies were no longer significantly different from vehicle-injected sites.

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