Itch is an unpleasant cutaneous sensation that can arise following insect bites, exposure to plant ingredients, and some diseases. Itch can also have idiopathic causes. Itch sensations are thought to protect against external insults and toxic substances. Although itch is not directly lethal, chronic and long lasting itch in certain diseases can worsen quality of life. Therefore, the mechanisms responsible for chronic itch require careful investigation. There is a significant amount of basic research concerning itch, and the effect of various itch mediators on primary sensory neurons have been studied. Interestingly, many mediators of itch involve signaling related to transient receptor potential (TRP) channels. TRP channels, especially thermosensitive TRP channels, are expressed by primary sensory neurons and skin keratinocytes, which receive multimodal stimuli, including those that cause itch sensations. Here we review the molecular and cellular mechanisms of itch and the involvement of TRP channels in mediating itch sensations.

Key pointsr Lysophosphatidic acid (LPA) is an itch mediator, but not a pain mediator by a cheek injection model.r Dorsal root ganglion neurons directly respond to LPA depending on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1).r LPA-induced itch-related behaviours are decreased in TRPA1-knockout (KO), TRPV1KO or TRPA1TRPV1 double KO mice. Abstract Intractable and continuous itch sensations often accompany diseases such as atopic dermatitis, neurogenic lesions, uremia and cholestasis. Lysophosphatidic acid (LPA) is an itch mediator found in cholestatic itch patients and it induces acute itch and pain in experimental rodent models. However, the molecular mechanism by which LPA activates peripheral sensory neurons remains unknown. In this study, we used a cheek injection method in mice to reveal that LPA induced itch-related behaviours but not pain-related behaviours. The LPA-induced itch behaviour and cellular effects were dependent on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which are important for itch signal transduction. We also found that, among the six LPA receptors, the LPA 5 receptor had the greatest involvement in itching. Furthermore, we demonstrated that phospholipase D (PLD) plays a critical role downstream of LPA 5 and that LPA directly and intracellularly activates TRPA1 and TRPV1. These results suggest a unique mechanism by which cytoplasmic LPA produced de novo could activate TRPA1 and TRPV1. We conclude that LPA-induced itch is mediated by LPA 5 , PLD, TRPA1 and TRPV1 signalling, and thus targeting TRPA1, TRPV1 or PLD could be effective for cholestatic itch interventions.