Sphingosine-1-Phosphate-Induced Nociceptor Excitation and Ongoing Pain Behavior in Mice and Humans Is Largely Mediated by S1P3 Receptor

Abstract

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 S1P-evoked 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.

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

“…A key function of S1P 1 and S1P 3 occurs during inflammatory disease processes through the promotion of astrogliosis (75,76). S1P receptor signaling induces nociceptive responses, possibly as a result of local increases of S1P, which are induced by injury or inflammation and sensed by S1P 3 (35,(77)(78)(79). Overall, the transport and biological functions of S1P in the nervous system are not well understood.…”

An update on the biology of sphingosine 1-phosphate receptors

“…Although analyses of entire mouse dorsal root ganglion found that S1P 3 was the most highly expressed S1PR, single cell mRNA analysis of individual neurons found that S1P 1 was most highly expressed, regardless of neuronal subtype, indicating that high expression of S1P 3 occurs in ganglion cell types other than neurons ( Fig. 5 ) ( 131,132 ). One group found that pain responses induced by intradermal S1P injection or models of postoperative pain were signifi cantly decreased in S1pr3 Ϫ / Ϫ mice, whereas minimal differences were seen in S1pr1 Ϫ / Ϫ mice ( 131 ); however, another group found that mice lacking S1P 1 specifi cally in nociceptor neurons were protected from S1P-induced pain ( 133 ).…”

Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors

“…For example, intra-as well as extracellular-applied S1P facilitates NGF-induced excitability of sensory neurons from dorsal root ganglia (DRG) (Zhang et al, 2006a,b) and induces thermal hyperalgesia (Mair et al, 2011). Accordingly, injection of S1P in peripheral tissue elicits hyperalgesic responses either directly through neuronal expressed S1P receptors S1P1 and S1P3 (Mair et al, 2011;Camprubi-Robles et al, 2013) or indirectly through immune cells such as neutrophil granulocytes (Finley et al, 2013).…”