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. 2012 Oct 17;32(42):14532-7.
doi: 10.1523/JNEUROSCI.3509-12.2012.

Mechanisms of itch evoked by β-alanine

Qin Liu  1 , Parul Sikand, Chao Ma, Zongxiang Tang, Liang Han, Zhe Li, Shuohao Sun, Robert H LaMotte, Xinzhong Dong
Affiliations

Mechanisms of itch evoked by β-alanine

Qin Liu et al. J Neurosci. .

Abstract

β-Alanine, a popular supplement for muscle building, induces itch and tingling after consumption, but the underlying molecular and neural mechanisms are obscure. Here we show that, in mice, β-alanine elicited itch-associated behavior that requires MrgprD, a G-protein-coupled receptor expressed by a subpopulation of primary sensory neurons. These neurons exclusively innervate the skin, respond to β-alanine, heat, and mechanical noxious stimuli but do not respond to histamine. In humans, intradermally injected β-alanine induced itch but neither wheal nor flare, suggesting that the itch was not mediated by histamine. Thus, the primary sensory neurons responsive to β-alanine are likely part of a histamine-independent itch neural circuit and a target for treating clinical itch that is unrelieved by anti-histamines.

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Figures

Figure 1.
Figure 1.
Intradermal injection of β-alanine evokes itch in humans. A, Time course of the mean perceived intensity of itch and nociceptive sensations evoked by intradermal injection of 90 μg (100 mm) of β-alanine or l-alanine. The mean ratings of itch, pricking/stinging, and burning obtained from 11 subjects are plotted for successive intervals of 30 s after injection. Beginning with the peak rating of each sensory quality, the SEM is plotted every 5 min (error bars). The positions of three verbal descriptors (vertical scale on the right) are shown in correspondence with the ratings of mean perceived intensity (y-axes). B, Time course of the mean perceived intensity of itch and nociceptive sensations evoked by different doses of β-alanine and l-alanine in the same subjects.
Figure 2.
Figure 2.
MrgprD is required for β-alanine-induced scratching in mice. A, Cheek injection of β-alanine induced site-directed scratching in WT but not MrgprD−/− mice. β-alanine induced significant scratching in WT mice during the first 15 min after injection in a dose-dependent manner (50 mm, n = 6; 20 mm, n = 5; 10 mm, n = 5). In contrast, few scratching bouts were detected in MrgprD−/− mice after β-alanine cheek injection (n = 5). l-alanine, the proteinogenic α-amino acid, did not induce a significant itch response (WT, n = 6; KO, n = 8). B, Orally administering β-alanine induced itch in WT but not MrgprD−/− (KO) mice. The total number of scratching bouts during the 40 min after β-alanine feeding (40 mg/kg body weight) was significantly higher in WT mice than in MrgprD−/− mice (n = 5 per genotype; *WT vs KO). All error bars represent SEM. *p < 0.05, **p < 0.01; Student's t test.
Figure 3.
Figure 3.
The response of DRG neurons to β-alanine is MrgprD-dependent. A, Approximately 12% of WT DRG neurons responded to β-alanine (β-ala; 1 mm) with increased [Ca2+]i, whereas MrgprD−/− DRG neurons did not respond (number of neurons analyzed: WT, n = 282; KO, n = 212, n = 3 mice per genotype). The response to histamine was not impaired in MrgprD−/− neurons. The percentage of MrgprD−/− neurons responding to histamine (100 μm) was similar to that of WT neurons (>300 neurons analyzed, 3–4 mice per genotype). Error bars represent SEM. B, Representative traces of DRG neurons from MrgprDGFP/+ mice in calcium imaging assays. β-alanine only activated GFP+ neurons as monitored by increased [Ca2+]i with calcium imaging. β-alanine-sensitive neurons (black, green, and blue traces; n = 91) did not respond to histamine (His; 100 μm) or CQ (1 mm), and histamine- and CQ-sensitive neurons (yellow, red, and orange traces) did not respond to β-alanine (>200 neurons from 3 mice). C, β-alanine (BA; 1 mm) induced action potentials in DRG neurons. In WT DRG, β-alanine-sensitive neurons (as determined by calcium imaging, n = 8) fired action potentials upon repeated β-alanine treatment. In contrast, none of the neurons tested from MrgprD−/− mice showed any response to the drug (n = 7).
Figure 4.
Figure 4.
β-alanine-sensitive neurons are C-mechanoheat nociceptive and do not respond to histamine. A, Bright-field image of a neuronal recording (arrow) with an extracellular electrode (outlined with dashed blue lines). B, Fluorescent microscopy revealed the expression of GFP (i.e., MrgprD+) in this neuron. C, Location of the cutaneous receptive field (red dot) of this neuron on the hairy skin of the hindpaw and conduction velocity (0.64 m/s, lower trace) obtained with electrical stimulation (arrow) of the receptive field. D, Responses of this neuron to a 60 mN force via a 200 μm diameter probe applied to the receptive field (1 s) with original extracellular recording trace (Ie) and action potentials (AP) indicated below. E, Response to heat stimulation (38–51°C, 5 s) indicates that this is a CMH nociceptive neuron. F, Responses of the above CMH neuron to the intradermal injection of vehicle (VEH), histamine (HIS), and β-alanine (BAL).
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References

    1. Baguet A, Koppo K, Pottier A, Derave W. Beta-alanine supplementation reduces acidosis but not oxygen uptake response during high-intensity cycling exercise. Eur J Appl Physiol. 2010;108:495–503. - PubMed
    1. Cavanaugh DJ, Lee H, Lo L, Shields SD, Zylka MJ, Basbaum AI, Anderson DJ. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci U S A. 2009;106:9075–9080. - PMC - PubMed
    1. Crush KG. Carnosine and related substances in animal tissues. Comp Biochem Physiol. 1970;34:3–30. - PubMed
    1. Décombaz J, Beaumont M, Vuichoud J, Bouisset F, Stellingwerff T. Effect of slow-release β-alanine tablets on absorption kinetics and paresthesia. Amino Acids. 2012;43:67–76. - PubMed
    1. Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell. 2001;106:619–632. - PubMed

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