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Published March 2, 2022 | Accepted Version + Supplemental Material
Journal Article Open

Glutamate in primary afferents is required for itch transmission


Whether glutamate or itch-selective neurotransmitters are used to confer itch specificity is still under debate. We focused on an itch-selective population of primary afferents expressing MRGPRA3, which highly expresses Vglut2 and the neuropeptide neuromedin B (Nmb), to investigate this question. Optogenetic stimulation of MRGPRA3+ afferents triggers scratching and other itch-related avoidance behaviors. Using a combination of optogenetics, spinal cord slice recordings, Vglut2 conditional knockout mice, and behavior assays, we showed that glutamate is essential for MRGPRA3+ afferents to transmit itch. We further demonstrated that MRGPRA3⁺ afferents form monosynaptic connections with both NMBR⁺ and NMBR⁻ neurons and that NMB and glutamate together can enhance the activity of NMBR⁺ spinal DH neurons. Moreover, Nmb in MRGPRA3⁺ afferents and NMBR⁺ DH neurons are required for chloroquine-induced scratching. Together, our results establish a new model in which glutamate is an essential neurotransmitter in primary afferents for itch transmission, whereas NMB signaling enhances its activities.

Additional Information

© 2021 Elsevier. Received 8 June 2020, Revised 21 August 2021, Accepted 6 December 2021, Available online 4 January 2022. We thank Dr. Yulong Li at Peking University for his insightful suggestions on experimental design. We thank the Johns Hopkins Transgenic Core for generating the Nmbr^(Cre) knockin mouse line and the Penn Skin Biology and Disease Resource-Based Center (Penn SBDRC) core facility for sectioning mouse skin samples. We thank Yi Gu at the National Institute of Neurological Disorders and Stroke as well as lab members in the Liu, Luo, and Ma labs for their help with the manuscript. This work is supported by NIH R01 grants (AI125743, AI163146, and EY024704) to Q.L. and NIH R01 grants (NS083702 and NS094224) to W.L. Author contributions. Conceptualization, L.C., M.M., Q.L., and W.L.; methodology, L.C., J.G., M.M., T.R., Q.L., and W.L.; investigation, L.C., J.G., S.L.C., M.G., J.B., K.B. W.O., R.C.C., Q.W., and X.S.; writing—original draft, L.C., S.L.C., and W.L.; writing—review and editing, L.C., S.L.C., M.M., Q.L., and W.L.; funding acquisition, Q.L. and W.L.; resources, W.L., Q.L., M.M., and V.G.; supervision, M.M., Q.L., and W.L. Declaration of interests. V.G. is a member of the Neuron Advisory Board. V.G. is also a cofounder and board member of Capsida Biotherapeutics, a fully integrated AAV engineering and gene therapy company. The other authors declare no competing interests. Inclusion and diversity. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. Data and code availability. All data reported in this paper will be shared by the lead contact upon request. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Attached Files

Accepted Version - nihms-1765076.pdf

Supplemental Material - 1-s2.0-S0896627321010151-mmc1.pdf

Supplemental Material - 1-s2.0-S0896627321010151-mmc2.mp4

Supplemental Material - 1-s2.0-S0896627321010151-mmc3.mp4

Supplemental Material - 1-s2.0-S0896627321010151-mmc4.mp4

Supplemental Material - 1-s2.0-S0896627321010151-mmc5.mp4


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Additional details

August 22, 2023
December 22, 2023