S1PR3 Mediates Itch and Pain via Distinct TRP Channel-Dependent Pathways (original) (raw)
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Journal of Neuroscience, 2013
The biolipid sphingosine-1-phosphate (S1P) is an essential modulator of innate immunity, cell migration, and wound healing. It is released locally upon acute tissue injury from endothelial cells and activated thrombocytes and, therefore, may give rise to acute posttraumatic pain sensation via a yet elusive molecular mechanism. We have used an interdisciplinary approach to address this question, and we find that intradermal injection of S1P induced significant licking and flinching behavior in wild-type mice and a dose-dependent flare reaction in human skin as a sign of acute activation of nociceptive nerve terminals. Notably, S1P evoked a small excitatory ionic current that resulted in nociceptor depolarization and action potential firing. This ionic current was preserved in "cation-free" solution and blocked by the nonspecific Cl Ϫ channel inhibitor niflumic acid and by preincubation with the G-protein inhibitor GDP--S. Notably, S1P 3 receptor was detected in virtually all neurons in human and mouse DRG. In line with this finding, S1P-induced neuronal responses and spontaneous pain behavior in vivo were substantially reduced in S1P 3 Ϫ/Ϫ mice, whereas in control S1P 1 floxed (S1P 1 fl/fl) mice and mice with a nociceptor-specific deletion of S1P 1 Ϫ/Ϫ receptor (SNS-S1P 1 Ϫ/Ϫ), neither the S1P-induced responses in vitro nor the S1Pevoked pain-like behavior was altered. Therefore, these findings indicate that S1P evokes significant nociception via G-proteindependent activation of an excitatory Cl Ϫ conductance that is largely mediated by S1P 3 receptors present in nociceptors, and point to these receptors as valuable therapeutic targets for post-traumatic pain.
Regulation of Pain and Itch by TRP Channels
Neuroscience bulletin, 2018
Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and finally members of the melastatin group (TRPM2, TRPM3, and TRPM8). Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory compounds targeting specific pain/itch-TRPs so that physiological protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1-modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accomplished via simple dosing strategie...
TRPA1 Channel is Involved in SLIGRL-Evoked Thermal and Mechanical Hyperalgesia in Mice
Medical Sciences, 2019
Persistent itch (pruritus) accompanying dermatologic and systemic diseases can significantly impair the quality of life. It is well known that itch is broadly categorized as histaminergic (sensitive to antihistamine medications) or non-histaminergic. Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch. These receptors have been shown to bind selective pruritogens in the periphery and mediate non-histaminergic itch. For example, mouse MrgprA3 responds to chloroquine (an anti-malarial drug), and are responsible for relaying chloroquine-induced scratching in mice. Mouse MrgprC11 responds to a different subset of pruritogens including bovine adrenal medulla peptide (BAM8–22) and the peptide Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL). On the other hand, the possibility that itch mediators also influence pain is supported by recent findings that most non-histaminergic itch mediators require the transient receptor potential ankyrin 1 (TRPA1)...
PLoS ONE, 2011
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 S1P 1 receptor for S1P is expressed in subpopulations of sensory neurons including nociceptors. Both S1P and agonists at the S1P 1 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 S1P 1 receptor. Our data show that neuronally expressed S1P 1 receptors play a significant role in regulating nociceptor function and that S1P/S1P 1 signaling may be a key player in the onset of thermal hypersensitivity and hyperalgesia associated with inflammation.
Neuroscience Letters, 2012
Sphingosine 1-phosphate (S1P) is a key immune mediator regulating migration of immune cells to sites of inflammation. S1P actions are mediated by a family of five G protein-coupled receptors. Sensory neurons express many of these receptors, and in vitro S1P has excitatory effects on smalldiameter sensory neurons, many mediated by the S1P receptor 1 (S1PR1). This study investigated the role of S1P in regulating the sensitivity of DRG neurons. We found that in vivo perfusion of the normal L5 DRG with S1P increased mechanical sensitivity. Microelectrode recordings in isolated whole ganglia showed that large-and medium-diameter cells, as well as small-diameter cells, increased firing in the presence of S1P. To further determine the role of S1PRs, we examined the effects of in vivo S1PR1 knockdown in the L4 and L5 sensory ganglia. Small interfering RNA directed against S1PR1 did not affect baseline mechanical sensitivity in normal animals, in which S1P levels are expected to be low. However, when the L5 ganglion was locally inflamed, a procedure that leads to rapid and sustained mechanical hypersensitivity, S1PR1 siRNA injected animals showed significantly less hypersensitivity than animals injected with scrambled siRNA. Reduced expression of S1PR1, but not S1PR2 or S1PR3, was confirmed with qPCR methods. The results indicate that the S1PR1 receptors in sensory ganglia cells may play an important role in regulating behavioral sensitivity during inflammation.
The signaling lipid sphingosine 1-phosphate regulates mechanical pain
eLife
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 excitab...
Pain Versus Itch: The Role of S1P
2019
Author(s): Awasthi, Shevya; Das, Doyel; Harari, Emily; Krishnapura, Ananya; Xiong, Michael; Lee, Rosa | Abstract: Interview with Dr. Diana Bautista
Pirt, a TRPV1 Modulator, Is Required for Histamine-Dependent and Independent Itch
PLOS One, 2011
Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood. Recent work has begun to identify genes that contribute to detecting itch at the molecular level. Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation. Pirt 2/2 mice exhibit deficits in cellular and behavioral responses to various itch-inducing compounds, or pruritogens. Pirt contributes to both histaminergic and nonhistaminergic itch and, crucially, is involved in forms of itch that are both TRPV1-dependent and -independent. Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways.
TRP channels as novel players in the pathogenesis and therapy of itch
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2007
Organization of the Review 1. Summary 2. Neurophysiology of itch 2.1. Basic phenomenon-Itch is "created" by our brain 2.2. Categories of itch 2.3. Theories of itch 2.4. The pruriceptive system 2.4.1. Pruriceptive primary afferent fibers 2.4.2. Spinal pruriceptive projection neurons and higher CNS structures involved in central processing of itch 2.4.3. Pruritogens-Mediators of itch 2.4.3.1. Histamine 2.4.3.2. SP and other neuropeptides 2.4.3.3. Inflammatory mediators as pruritogens-Peripheral sensitization of itch by arachidonic acid derivatives, kinins, and interleukins 2.4.3.4. Proteases and their receptors 2.4.3.5. NGF and certain neurotrophins-Acute and chronic itch sensitizers 3. TRP channels-"TRiPping" novel players in pruritus pathogenesis 3.1. Why TRP channels? 3.2. TRPV1-A t hermosensitive channel with a central role in the pathogenesis and therapy of itch 3.2.1. TRPV1-A "hot and spicy" target of capsaicin on sensory neurons 3.2.2. "Endovanilloids"-The "itch connection" 3.2.3. TRPV1 on non-neuronal cell types of the skin-Other "itchy" findings to explore 3.2.4. Therapeutic implications-The vanilloid-TRPV1 system to mitigate itch 3.2.4.1 Capsaicin and related exovanilloids 3.2.4.2. Cannabinoids and TRPV1-The challenge of getting the skin "high", rather than "itchy" 3.2.4.3. Physical methods to target TRPV1-"Burning itch with fire"? 3.3. Other thermosensitive TRP channels as novel players in pruritus 3.3.1. TRPV2, TRPV3, and TRPV4-More "hot" is coming to fight itch 3.3.2. TRPM8-A "cool" anti-itch agent 3.3.3. TRPA1-A "pungent ic(e)ing on the cake" 3.3.4. Temperature-sensitive TRP channels establish a basic syntax and molecular substrate of nociception and pruriception-The "molecular psychophysics" of itch and pain sensation 3.4. Other non-thermosensitive TRP channels-Distant connections to pruritus 3.4.1. TRPCs-Itch modulation via altered keratinocyte differentiation? 3.4.2. TRPM6 and TRPM7-Itch and the magnesium connection 4. Conclusions, future perspectives 5. References 6. Tables