scholarly journals The signaling lipid sphingosine 1-phosphate regulates mechanical pain

2017 ◽  
Author(s):  
Rose Z. Hill ◽  
Benjamin U. Hoffman ◽  
Takeshi Morita ◽  
Stephanie M. Campos ◽  
Ellen A. Lumpkin ◽  
...  
Keyword(s):  
Behavioral Response ◽  
Neuronal Excitability ◽  
Mutant Mice ◽  
Mechanical Stimuli ◽  
Pain Thresholds ◽  
Somatosensory Neurons ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Mechanical Pain Thresholds ◽  
Thermal Stimuli

AbstractSomatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds.

scholarly journals The signaling lipid sphingosine 1-phosphate regulates mechanical pain

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Rose Z Hill ◽  
Benjamin U Hoffman ◽  
Takeshi Morita ◽  
Stephanie M Campos ◽  
Ellen A Lumpkin ◽  
...  
Keyword(s):  
Behavioral Response ◽  
Neuronal Excitability ◽  
Mutant Mice ◽  
Mechanical Stimuli ◽  
Pain Thresholds ◽  
Somatosensory Neurons ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Mechanical Pain Thresholds ◽  
Thermal Stimuli

Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds.

scholarly journals Expression of sphingosine 1-phosphate receptors in the rat dorsal root ganglia and defined single isolated sensory neurons

2012 ◽  
Vol 44 (18) ◽  
pp. 889-901 ◽  
Author(s):  
J. S. Kays ◽  
Chao Li ◽  
G. D. Nicol
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root ◽  
Neuronal Excitability ◽  
Expression Profiles ◽  
Large Diameter ◽  
Small Diameter ◽  
Positive Control ◽  
Single Neurons ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Previously, we demonstrated that sphingosine 1-phosphate (S1P) increased the excitability of small-diameter sensory neurons, in part, through activation of S1P receptor 1 (S1PR1), suggesting that other S1PRs can modulate neuronal excitability. Therefore, studies were undertaken to establish the expression profiles of S1PRs in the intact dorsal root ganglion (DRG) and in defined single isolated sensory neurons. To determine mRNA expression of S1PRs in the DRG, SYBR green quantitative PCR (qPCR) was used. To determine the expression of S1PR mRNAs in single neurons of defined diameters, a preamplification protocol utilizing Taqman primer and probes was used to enhance the sensitivity of detection. The preamplification protocol also permitted detection of mRNA for two hallmark neuronal receptor/ion channels, TRPV1 and P2X3. Expression profiles of S1PR mRNA isolated from lung and brain were used as positive control tissues. In the intact DRG, the order of expression of S1PRs was S1PR3>>R1≈R2>R5≈R4. In the single neurons, the expression of S1PRs was quite variable with some neurons expressing all five subtypes, whereas some expressing only one subtype. In contrast to the DRG, S1PR1 was the highest expressing subtype in 10 of the 18 small-, medium-, and large-diameter sensory neurons. S1PR1 was the second highest expressor in ∼50% of those remaining neurons. Overall, in the single neurons, the order of expression was S1PR1>>R3≈R5>R4>R2. The results obtained from the single defined neurons are consistent with our previous findings wherein S1PR1 plays a prominent but not exclusive role in the enhancement of neuronal excitability.

Hyperalgesia in human skin and deep-tissues inside and outside of a UVB irradiated area

2012 ◽  
Vol 3 (3) ◽  
pp. 190-190 ◽  
Author(s):  
Silvia Lo Vecchio ◽  
Lars J. Petersen ◽  
Thomas Graven-Nielsen ◽  
Sara Finocchietti ◽  
Parisa Gazerani ◽  
...  
Keyword(s):  
Blood Flow ◽  
Human Skin ◽  
Mechanical Stimuli ◽  
Deep Tissue ◽  
Tissue Pressure ◽  
Pain Thresholds ◽  
Pressure Pain ◽  
Uvb Irradiation ◽  
Pressure Pain Thresholds ◽  
Mechanical Pain Thresholds

Abstract Background/aims The ultraviolet B (UVB) inflammatory pain model is often used to induce a steady hyperalgesic area in human skin. UVB causes a well-described erythema, developing maximal response within about 24 h. The aim of the present study was to investigate if cutaneous UVB irradiation can influence both superficial and deep-tissue mechanical pain thresholds in the site of irradiation and in the surrounding area. Methods An area of 3 cm × 4 cm, located on the low back of 16 healthy volunteers, was irradiated by UVB (Medlight, Germany; 3xMED: Minimal Erythema Dose). The degree of inflammation was detected by measuring superficial blood flow before and after irradiation, inside and outside the stimulated area. Applying quantitative sensory assessments, mechanical pain threshold changes were detected one day after irradiation, within and outside of the irradiated area. Sensitivity to cutaneous mechanical stimuli was assessed using pin prick and deep-tissue pressure pain thresholds were evaluated on 12 spots (4 within and 8 outside, 1.5 cm distant from the irradiated area) by a computer-controlled pressure algometer (Aalborg University, Denmark; 1.0 cm2 flat probe, 0.5 cm2 flat probe and a V-shaped probe with a contact surface of 0.03 cm2). Results 24 h after exposure, the irradiated skin showed clear erythema with a boundary matching the irradiated area and a statistically significant increase in cutaneous blood flow (P < 0.001) compared with baseline assessment. Cutaneous pin prick pain thresholds and deep-tissue pressure pain thresholds (all probes) were significantly decreased inside and outside the irradiated area (P < 0.05). Conclusions Cutaneous UVB irradiation reduces mechanical pain thresholds to pin-prick and pressure stimulation which may indicate allodynic responses in both the skin and in deep-tissues. Expansion of the responses to areas outside the irradiated zone confirmed the presence of secondary hyperalgesia to mechanical stimuli.

scholarly journals Episodic and chronic migraineurs are hypersensitive to thermal stimuli between migraine attacks

Cephalalgia ◽  
2010 ◽  
Vol 31 (1) ◽  
pp. 6-12 ◽  
Author(s):  
Todd J Schwedt ◽  
Melissa J Krauss ◽  
Karen Frey ◽  
Robert W Gereau
Keyword(s):  
Quantitative Sensory Testing ◽  
Pain Tolerance ◽  
Sensory Testing ◽  
Cold Pain ◽  
Pain Thresholds ◽  
Thermal Pain ◽  
Mechanical Pain Thresholds ◽  
Thermal Stimuli ◽  
Episodic Migraineurs ◽  
Chronic Migraineurs

Objective: To determine if migraineurs have evidence of interictal cutaneous sensitisation. Subjects and methods: Thermal and mechanical pain thresholds in 20 episodic migraineurs, 20 chronic migraineurs, and 20 non-migraine control subjects were compared. Quantitative sensory testing was conducted when subjects had been migraine-free for at least 48 h. Heat, cold and mechanical pain thresholds, and heat and cold pain tolerance thresholds were measured. Results: Thermal pain thresholds and thermal pain tolerance thresholds differed significantly by headache group ( P = 0.001). During the interictal period, episodic and chronic migraineurs were more sensitive to thermal stimulation than non-migraine controls. Conclusions: Interictal sensitisation may predispose the migraineur to development of headaches, may be a marker of migraine activity, and a target for treatment.

scholarly journals Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

2004 ◽  
Vol 279 (50) ◽  
pp. 52487-52492 ◽  
Author(s):  
Maria L. Allende ◽  
Teiji Sasaki ◽  
Hiromichi Kawai ◽  
Ana Olivera ◽  
Yide Mi ◽  
...  
Keyword(s):  
Vascular Development ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Cellular Functions ◽  
Lymphocyte Trafficking ◽  
Signaling Molecule ◽  
Physiological Functions ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
S1p Receptor

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

scholarly journals Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate

2004 ◽  
Vol 279 (14) ◽  
pp. 13839-13848 ◽  
Author(s):  
M. Germana Sanna ◽  
Jiayu Liao ◽  
Euijung Jo ◽  
Christopher Alfonso ◽  
Min-Young Ahn ◽  
...  
Keyword(s):  
Heart Rate ◽  
Receptor Subtypes ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Lymphocyte Recirculation

scholarly journals Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss

2021 ◽  
Vol 9 ◽  
Author(s):  
Cheryl L. San Emeterio ◽  
Lauren A. Hymel ◽  
Thomas C. Turner ◽  
Molly E. Ogle ◽  
Emily G. Pendleton ◽  
...  
Keyword(s):  
Muscle Loss ◽  
Muscle Injuries ◽  
Bioactive Lipids ◽  
Muscle Stem Cells ◽  
Receptor Modulation ◽  
Volumetric Muscle Loss ◽  
Signaling Axis ◽  
Repair Mechanisms ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Volumetric muscle loss (VML) injuries after extremity trauma results in an important clinical challenge often associated with impaired healing, significant fibrosis, and long-term pain and functional deficits. While acute muscle injuries typically display a remarkable capacity for regeneration, critically sized VML defects present a dysregulated immune microenvironment which overwhelms innate repair mechanisms leading to chronic inflammation and pro-fibrotic signaling. In this series of studies, we developed an immunomodulatory biomaterial therapy to locally modulate the sphingosine-1-phosphate (S1P) signaling axis and resolve the persistent pro-inflammatory injury niche plaguing a critically sized VML defect. Multiparameter pseudo-temporal 2D projections of single cell cytometry data revealed subtle distinctions in the altered dynamics of specific immune subpopulations infiltrating the defect that were critical to muscle regeneration. We show that S1P receptor modulation via nanofiber delivery of Fingolimod (FTY720) was characterized by increased numbers of pro-regenerative immune subsets and coincided with an enriched pool of muscle stem cells (MuSCs) within the injured tissue. This FTY720-induced priming of the local injury milieu resulted in increased myofiber diameter and alignment across the defect space followed by enhanced revascularization and reinnervation of the injured muscle. These findings indicate that localized modulation of S1P receptor signaling via nanofiber scaffolds, which resemble the native extracellular matrix ablated upon injury, provides great potential as an immunotherapy for bolstering endogenous mechanisms of regeneration following VML injury.

scholarly journals Progressive recruitment of distal MEC-4 channels determines touch response strength in C. elegans

2019 ◽  
Author(s):  
S. Katta ◽  
A. Sanzeni ◽  
A. Das ◽  
M. Vergassola ◽  
M.B. Goodman
Keyword(s):  
Temporal Dynamics ◽  
Mechanical Strain ◽  
Tissue Mechanics ◽  
Mechanical Stimuli ◽  
Patch Clamp Recording ◽  
Open Probability ◽  
C Elegans ◽  
Somatosensory Neurons ◽  
Touch Response

AbstractTouch deforms, or strains, the skin beyond the immediate point of contact. The spatiotemporal nature of the touch-induced strain fields depend on the mechanical properties of the skin and the tissues below. Somatosensory neurons that sense touch branch out within the skin and rely on a set of mechano-electrical transduction channels distributed within their dendrites to detect mechanical stimuli. Here, we sought to understand how tissue mechanics shape touch-induced mechanical strain across the skin over time and how individual channels located in different regions of the strain field contribute to the overall touch response. We leveraged C. elegans’ touch receptor neurons (TRNs) as a simple model amenable to in vivo whole-cell patch clamp recording and an integrated experimental-computational approach to dissect the mechanisms underlying the spatial and temporal dynamics that we observed. Consistent with the idea that strain is produced at a distance, we show that delivering strong stimuli outside the anatomical extent of the neuron is sufficient to evoke MRCs. The amplitude and kinetics of the MRCs depended on both stimulus displacement and speed. Finally, we found that the main factor responsible for touch sensitivity is the recruitment of progressively more distant channels by stronger stimuli, rather than modulation of channel open probability. This principle may generalize to somatosensory neurons with more complex morphologies.SummaryThrough experiment and simulation, Katta et al. reveal that pushing faster and deeper recruits more and more distant mechano-electrical transduction channels during touch. The net result is a dynamic receptive field whose size and shape depends on tissue mechanics, stimulus parameters, and channel distribution within sensory neurons.

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