Additionally, recent studies have shown that S1PRs are expressed throughout the nervous system ( Janes et al., 2014 Mair et al., 2011 Camprubí-Robles et al., 2013) and S1P signaling is associated with a variety of neuroinflammatory disorders, including multiple sclerosis ( Brinkmann et al., 2010) and Alzheimer’s disease ( Couttas et al., 2014). S1P signaling, mainly via S1PR1, plays a well-known role in immune cell migration and maturation ( Spiegel and Milstien, 2003 Matloubian et al., 2004 Schwab et al., 2005). S1P is a bioactive lipid that signals via 5 G-protein coupled S1P Receptors (S1PRs 1–5). Here, we show that sphingosine 1-phosphate (S1P) is required for mechanical pain sensation. ![]() Despite these advances in defining the cells and circuits of mechanical pain, little is known about the molecular signaling pathways in mechanonociceptors. Additionally, somatostatin-expressing interneurons of laminae I-III in the dorsal horn of the spinal cord receive input from nociceptors and are required for behavioral responses to painful mechanical stimuli ( Duan et al., 2014). The Calca + subpopulation of circumferential-HTMRs responds to noxious force and hair pulling, and terminates as circumferential endings wrapped around guard hair follicles ( Ghitani et al., 2017). The Npy2r + subpopulation of HTMRs mediates fast paw withdrawal responses to pinprick stimulation and terminates as free nerve endings in the epidermis ( Arcourt et al., 2017). Recent studies have shown that there are at least two populations of HTMRs that mediate responses to noxious mechanical stimuli. Aδ high-threshold mechanoreceptors (HTMRs) have been shown to play a key role in responses to painful mechanical stimuli ( Arcourt et al., 2017 Ghitani et al., 2017). Thermal pain is detected by thermosensitive TRP channels in subsets of nociceptors ( Caterina et al., 2000 Vriens et al., 2011), and gentle touch is detected by Piezo2 channels in low-threshold mechanoreceptors (LTMRs) ( Ranade et al., 2014 Woo et al., 2014). Distinct cells and molecules detect noxious thermal and mechanical stimuli. It serves to protect organisms from harmful stimuli, but can also become chronic and debilitating following tissue injury and disease. 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. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. ![]() 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. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain.
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