Our findings indicate that skin sensations evoked by β-alanine are mediated by MrgprD expressed in cutaneous sensory neurons. Although another study showed that MrgprD enhanced the excitability of small-diameter DRG neurons (Rau et al., 2009
), its function in somatosensation has not been directly demonstrated. In this study, we provide the first evidence that β-alanine can directly trigger action potentials in both in vitro
cultures and in vivo
DRG neuron recordings. Furthermore, our mouse behavioral and human psychophysical data suggest that a major role of MrgprD in somatosensation is itch. These studies provide a molecular explanation for β-alanine-induced itch and demonstrate that β-alanine -induced itch-mediating neural activity originates in the peripheral- and not central nervous system.
β-alanine sensitivity defines a unique population of itch-mediating neurons and further demonstrates the functional diversity of primary sensory neurons in DRG. MrgprD-expressing neurons comprise a majority of non-peptidergic, small-diameter neurons in the DRG. Dissociated DRG neuron recordings, skin nerve recordings, and neuronal ablation studies suggest MrgprD+
neurons are un-myelinated (C-fiber), mechanosensitive nociceptive neurons (Dussor et al., 2008
; Cavanaugh et al., 2009
; Rau et al., 2009
). Behaviorally, mice lacking MrgprD+
neurons exhibit reduced mechanical but not thermal pain, suggesting MrgprD+
neurons are mainly involved in mechano-sensation in vivo
(Cavanaugh et al., 2009
). Here we reveal the unexpected heterogeneity and functional diversity of MrgprD+
neurons. Only a subset of MrgprD-expressing neurons is involved in β-alanine evoked itch. Interestingly, this subset has physiological properties distinct from those of β-alanine -insensitive but MrgprD+
neurons. In vivo
DRG recordings showed that β-alanine -sensitive neurons account for ~40% of total MrgprD-expressing neurons and respond to heat stimuli. By contrast, the β-alanine -insensitive but MrgprD+
neurons are insensitive to heat. In the future, it would be interesting to investigate the molecular basis of the distinct physiological properties of MrgprD-expressing neurons. Furthermore, β-alanine sensitivity implies a functional diversity of MrgprD-expressing neurons and raises the question of whether a fraction of MrgprD-expressing neurons are dedicated to the transduction of pruritic chemicals and mediate itch whereas others might mediate mechanically evoked pain. Our data are consistent with the presence of two different types of itch mediating neurons, one responsive to β-alanine but not to histamine and another responsive to histamine but not MrgprD+
(Liu et al., 2009
). The MrgprD molecular marker coupled with the response to β-alanine provide a means of identifying the same itch-mediating neurons in vitro and in vivo.
Our studies also developed a novel, physiologically relevant method to study itch. Most if not all current animal models of acute itch entail skin injection of itch-inducing compounds. However, most drug-, supplement-, and food-induced itch are triggered by oral consumption. Oral administration of β-alanine provides a valuable way to study itch, especially for investigating itch side effects caused by many orally taken medicines (Reich et al., 2009
). Because only healthy volunteers were tested it remains to be determined whether the levels of β-alanine or some other endogenous chemical mediator may be capable of activating MrgprD expressing neurons and contribute to itch under pathological conditions. Taken together, the identification of MrgprD as an itch-mediating receptor should open new avenues for the exploration of pruriceptive neuronal function and circuitry as well as the development of novel anti-pruritic drugs.