Dorsal root ganglion neurons respond to both painful and itchy stimuli, but whether itch-specific neurons exist was, up until now, unknown. Here the authors describe a group of MrgprA3-expressing neurons that innervate the superficial layers of the skin and selectively sense itch. Itch-specific neurons have been sought for decades. The existence of such neurons has been doubted recently as a result of the observation that itch-mediating neurons also respond to painful stimuli. We genetically labeled and manipulated MrgprA3+ neurons in the dorsal root ganglion (DRG) and found that they exclusively innervated the epidermis of the skin and responded to multiple pruritogens. Ablation of MrgprA3+ neurons led to substantial reductions in scratching evoked by multiple pruritogens and occurring spontaneously under chronic itch conditions, whereas pain sensitivity remained intact. Notably, mice in which TRPV1 was exclusively expressed in MrgprA3+ neurons exhibited itch, but not pain, behavior in response to capsaicin. Although MrgprA3+ neurons were sensitive to noxious heat, activation of TRPV1 in these neurons by noxious heat did not alter pain behavior. These data suggest that MrgprA3 defines a specific subpopulation of DRG neurons mediating itch. Our study opens new avenues for studying itch and developing anti-pruritic therapies.

Sensory neurons perceive itch and heat-induced pain through two different receptors.

In primates, C-fibre polymodal nociceptors are broadly classified into two groups based on mechanosensitivity. Here we demonstrate that mechanically sensitive polymodal nociceptors that respond either quickly (QC) or slowly (SC) to a heat stimulus differ in responses to a mild burn, heat sensitization, conductive properties and chemosensitivity. Superficially applied capsaicin and intradermal injection of β-alanine, an MrgprD agonist, excite vigorously all QCs. Only 40% of SCs respond to β-alanine, and their response is only half that of QCs. Mechanically insensitive C-fibres (C-MIAs) are β-alanine insensitive but vigorously respond to capsaicin and histamine with distinct discharge patterns. Calcium imaging reveals that β-alanine and histamine activate distinct populations of capsaicin-responsive neurons in primate dorsal root ganglion. We suggest that histamine itch and capsaicin pain are peripherally encoded in C-MIAs, and that primate polymodal nociceptive afferents form three functionally distinct subpopulations with β-alanine responsive QC fibres likely corresponding to murine MrgprD-expressing, non-peptidergic nociceptive afferents.

Pirt is a membrane protein that is specifically expressed in the peripheral nervous system, where it has been shown to increase the sensitivity of the transient receptor potential vanilloid 1 channel and modulate its role in heat pain. The broad expression of Pirt among dorsal root ganglion neurons suggests it may modulate other transient receptor potentials, such as the menthol and cooling sensor TRPM8. The discrepancies in the channel properties of TRPM8 in native neurons versus heterologous cells indicate the existence of endogenous modulators of the channel. Here we show that Pirt regulates the function of TRPM8 and its role in detecting cold. Pirt^−/− mice exhibit decreased behavioural responses to cold and cool temperatures, and Pirt increases the sensitivity of TRPM8 to menthol and cool temperature. Our data suggest Pirt is an endogenous regulator of TRPM8.