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Abstract: Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors, eg, from the Mas-related G-protein-coupled receptor family. Human nerve fibers involved in pain signaling ("nociceptors") can elicit itch if activated by focalized stimuli such as cowhage spicules. In this study, we scrutinized the effects of LPA in humans by 2 different application modes on the level of psychophysics and single nerve fiber recordings (microneurography). In healthy human subjects, intracutaneous LPA microinjections elicited burning pain, whereas LPA application through inactivated cowhage spicules evoked a moderate itch sensation. Lysophosphatidic acid microinjections induced heat hyperalgesia and hypersensitivity to higher electrical stimulus frequencies. Pharmacological blockade of transient receptor potential channel A1 or transient receptor potential channel vanilloid 1 reduced heat hyperalgesia, but not acute chemical pain. Microneurography revealed an application mode-dependent differential activation of mechanosensitive (CM) and mechanoinsensitive C (CMi) fibers. Lysophosphatidic acid microinjections activated a greater proportion of CMi fibers and more strongly than CM fibers; spicule application of LPA activated CM and CMi fibers to a similar extent but excited CM fibers more and CMi fibers less intensely than microinjections. In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents and a specific combination of activated fiber subclasses might contribute., (Copyright © 2021 International Association for the Study of Pain.)