Differential contribution of sensory transient receptor potential channels in response to the bioactive lipid sphingosine-1-phosphate

Abstract

Somatosensation encompasses a wide range of sensations including pain, itch, touch, and temperature and is essential for the detection of environmental stimuli, ultimately allowing an organism to escape, communicate, and adapt to its environment. Such sensations are detected by primary sensory neurons whose nerve endings are located in the skin. Compared to external stimuli, mechanisms underlying endogenous stimulation of primary sensory neurons, such as by lipids, are still largely unknown. Here, we focus on one of the endogenous bioactive lipids, sphingosine-1-phosphate (S1P), to investigate the physiological roles of S1P in pain and itch. We showed that S1P-induced calcium responses in sensory neurons through S1P receptors. Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are nonselective calcium-permeable ion channels that are known to be involved in pain and itch. Neurons that respond to S1P show reduced responsiveness when treated with antagonists that block either TRPA1 or TRPV1 alone or in combination. In addition, using single and double knockout mice (TRPA1; TRPV1; TRPA1/TRPV1) with loss of function of these channels, we demonstrated that both TRP channels are involved in S1P-induced neuronal responses in vitro. Next, we examined the effects of S1P on pain and itch responsiveness in freely behaving mice post-S1P injection into the cheek, neck, and hind paw. Our findings reveal that S1P induces both pain and itch in vivo and that these responses are partially dependent upon the TRPV1, but not TRPA1 channels.

Targeting the Sphingosine-1-Phosphate Axis for Developing Non-narcotic Pain Therapeutics

“…In TRPA1 -/ TRPV1 + neurons, S1P trigger S1PR3-Gαq signaling, leading to phospholipase C (PLC) phosphorylation and activation of TRPV1 receptors (Figure 3) [61]. A recent study, even if mostly in accordance with the earlier-mentioned results, reported a major involvement of TRPV1 over TRPA1 in S1P-mediated pain and itch [62].…”

Neuroinflammatory gene expression analysis reveals potential novel mediators and treatment targets in interstitial cystitis with Hunner lesions

“…Kittaka et al have demonstrated a potential link between TRPA1 and S1PR (27). S1P-induced responses in the dorsal root ganglia neurons in mice were partially inhibited by TRPA1 antagonists.…”

Novel functions of S1P in chronic itchy and inflammatory skin diseases

“…Another study on the subject, which was published in 2020 by Kittaka et al 44 . also showed significant downstream involvement of the two transient receptor potential channels in S1P signalling‐mediated pain and itch, making them an interesting topic for future research.…”

“…Further experiments such as Ca 2+ imaging and knockout animal models for TRPA1 and TRPV1, showed that the sensations were mediated through S1PR3 to TRPA1 and TRPV1, with TRPV1 being responsible for acute pain and heat hypersensitivity and TRPA1 mediating itch. 38 Another study on the subject, which was published in 2020 by Kittaka et al 44 also showed significant downstream involvement of the two transient receptor potential channels in S1P signalling-mediated pain and itch, making them an interesting topic for future research.…”