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Despite its clinical importance, the underlying neural mechanisms of itch sensation are poorly understood. In many diseases, pruritus is not effectively treated with antihistamines, indicating the involvement of non-histaminergic mechanisms. To investigate the role of small myelinated afferents in non-histaminergic itch, we tested, in psychophysical studies in humans, the effect of a differential nerve block on itch produced by intradermal insertion of spicules from the pods of a cowhage plant (Mucuna pruriens). Electrophysiological experiments in anesthetized monkey were used to investigate the responsiveness of cutaneous, nociceptive, myelinated afferents to different chemical stimuli (cowhage spicules, histamine, capsaicin). Our results provide several lines of evidence for an important role of myelinated fibers in cowhage-induced itch: 1) a selective conduction block in myelinated fibers substantially reduces itch in a sub-group of subjects with A-fiber dominated itch, 2) the time course of itch sensation differs between subjects with A-fiber versus C-fiber dominated itch, 3) cowhage activates a subpopulation of myelinated and unmyelinated afferents in monkey, 4) the time course of the response to cowhage is different in myelinated and unmyelinated fibers, 5) the time of peak itch sensation for subjects with A-fiber dominated itch matches the time for peak response in myelinated fibers, and 6) the time for peak itch sensation for subjects with C-fiber dominated itch matches the time for the peak response in unmyelinated fibers. These findings demonstrate that activity in nociceptive, myelinated afferents contributes to cowhage-induced sensations, and that non-histaminergic itch is mediated through activity in both unmyelinated and myelinated afferents.

Cutaneous thermosensation plays an important role in thermal regulation and detection of potentially harmful thermal stimuli. Multiple classes of primary afferents are responsive to thermal stimuli. Afferent nerve fibers mediating the sensation of non-painful warmth or cold seem adapted to convey thermal information over a particular temperature range. In contrast, nociceptive afferents are often activated by both, painful cold and heat stimuli. The transduction mechanisms engaged by thermal stimuli have only recently been discovered. Transient receptor potential (TRP) ion channels that can be activated by temperatures over specific ranges potentially provide the molecular basis for thermosensation. However, non-TRP mechanisms are also likely to contribute to the transduction of thermal stimuli. This review summarizes findings regarding the transduction proteins and the primary afferents activated by innocuous and noxious cold and heat.