sphingosine-1-phosphate and Pain

Approximately 20% of the population in Western countries suffers from chronic pain syndromes for which treatments are frequently insufficient or non-existent. In particular, chronic pain management with opiate/narcotic analgesics is often hampered by the development of analgesic tolerance and hyperalgesia, necessitating escalating doses to achieve pain relief. There is a major need for renewed focus on novel targets that will be effective in both neuropathic and inflammatory pain. Compelling evidence implicates ceramide-to-sphingosine 1-phosphate (S1P) pathways as contributors to pain of diverse etiologies. Moreover, S1P and its receptors are emerging as important neuronal and immune cell regulators interacting at several sites in the pain pathway. It is therefore timely and important to critically evaluate the pharmacological basis for targeting the ceramide-to-S1P pathway as an approach to pain management.

Topics: Analgesics; Animals; Ceramides; Humans; Lysophospholipids; Metabolic Networks and Pathways; Molecular Targeted Therapy; Pain; Sphingosine

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 post-traumatic 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(-) channel inhibitor niflumic acid and by preincubation with the G-protein inhibitor GDP-β-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)(-/-) mice, whereas in control S1P(1) floxed (S1P(1)(fl/fl)) mice and mice with a nociceptor-specific deletion of S1P(1)(-/-) receptor (SNS-S1P(1)(-/-)), neither the S1P-induced responses in vitro nor the S1P-evoked pain-like behavior was altered. Therefore, these findings indicate that S1P evokes significant nociception via G-protein-dependent activation of an excitatory Cl(-) 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.

Topics: Adult; Animals; Cells, Cultured; Double-Blind Method; Female; Ganglia, Spinal; Humans; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; Pain Measurement; Receptors, Lysosphingolipid; Sphingosine

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.

Topics: Animals; Cells, Cultured; Ganglia, Spinal; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Lysophospholipids; Mechanoreceptors; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pain; Pain Threshold; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid associated with a variety of chronic pain and itch disorders. S1P signaling has been linked to cutaneous pain, but its role in itch has not yet been studied. Here, we find that S1P triggers itch and pain in male mice in a concentration-dependent manner, with low levels triggering acute itch alone and high levels triggering both pain and itch. Ca

Topics: Animals; Calcium; Lysophospholipids; Mice; Mice, Knockout; Pain; Pruritus; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; TRPV Cation Channels

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.

Topics: Animals; Hot Temperature; Hyperalgesia; Inflammation; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nociceptors; Pain; Receptors, Lysosphingolipid; Sensory Receptor Cells; Signal Transduction; Skin; Sphingosine

Sphingosine 1-Phosphate (S1P) modulates various cellular functions such as apoptosis, cell differentiation, and migration. Although S1P is an abundant signaling molecule in the central nervous system, very little is known about its influence on neuronal functions. We found that S1P concentrations were selectively decreased in the cerebrospinal fluid of adult rats in an acute and an inflammatory pain model. Pharmacological inhibition of sphingosine kinases (SPHK) decreased basal pain thresholds and SphK2 knock-out mice, but not SphK1 knock-out mice, had a significant decrease in withdrawal latency. Intrathecal application of S1P or sphinganine 1-phosphate (dihydro-S1P) reduced the pain-related (nociceptive) behavior in the formalin assay. S1P and dihydro-S1P inhibited cyclic AMP (cAMP) synthesis, a key second messenger of spinal nociceptive processing, in spinal cord neurons. By combining fluorescence resonance energy transfer (FRET)-based cAMP measurements with Multi Epitope Ligand Cartography (MELC), we showed that S1P decreased cAMP synthesis in excitatory dorsal horn neurons. Accordingly, intrathecal application of dihydro-S1P abolished the cAMP-dependent phosphorylation of NMDA receptors in the outer laminae of the spinal cord. Taken together, the data show that S1P modulates spinal nociceptive processing through inhibition of neuronal cAMP synthesis.

Topics: Animals; Behavior, Animal; Cyclic AMP; Fluorescence Resonance Energy Transfer; Lysophospholipids; Mice; Mice, Knockout; Neurons; Pain; Phosphotransferases (Alcohol Group Acceptor); Rats; Rats, Sprague-Dawley; Signal Transduction; Sphingosine; Spine