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Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors

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Abstract

Mechanical pain contributes to the morbidity associated with inflammation and trauma, but primary sensory neurons that convey the sensation of acute and persistent mechanical pain have not been identified. Dorsal root ganglion (DRG) neurons transmit sensory information to the spinal cord using the excitatory transmitter glutamate1, a process that depends on glutamate transport into synaptic vesicles for regulated exocytotic release. Here we report that a small subset of cells in the DRG expresses the low abundance vesicular glutamate transporter VGLUT3 (also known as SLC17A8). In the dorsal horn of the spinal cord, these afferents project to lamina I and the innermost layer of lamina II, which has previously been implicated in persistent pain caused by injury2. Because the different VGLUT isoforms generally have a non-redundant pattern of expression3, we used Vglut3 knockout mice to assess the role of VGLUT3+ primary afferents in the behavioural response to somatosensory input. The loss of VGLUT3 specifically impairs mechanical pain sensation, and in particular the mechanical hypersensitivity to normally innocuous stimuli that accompanies inflammation, nerve injury and trauma. Direct recording from VGLUT3+ neurons in the DRG further identifies them as a poorly understood population of unmyelinated, low threshold mechanoreceptors (C-LTMRs)4,5. The analysis of Vglut3-/- mice now indicates a critical role for C-LTMRs in the mechanical hypersensitivity caused by injury.

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Figure 1: VGLUT3 is expressed by a unique subset of small- and medium-sized DRG neurons that project to dorsal horn lamina I and the inner part of lamina II.
Figure 2: Vglut3 -/- mice show a selective defect in acute mechanical pain sensation to intense noxious stimuli.
Figure 3: Vglut3 -/- mice show a profound, selective defect in the mechanical hypersensitivity produced by inflammation, nerve injury and trauma.
Figure 4: VGLUT3 expression in DRG uniquely identifies C-LTMRs.

Change history

  • 03 December 2009

    Three minor changes were made to the Figure 4 legend on 3 December 2009.

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Acknowledgements

We thank D. Bautista, D. Julius and members of the Basbaum and Edwards laboratories for advice, and D. Woodbury and C. Cassidy from the Woodbury laboratory for help with experiments. The work was supported by the Johns Hopkins Blaustein Pain Research Fund (Y.G.) and by grants from NARSAD (R.P.S., R.H.E.) and NIH (R.P.S., Y.G., S.N.R., C.J.W., A.I.B. and R.H.E.).

Author Contributions R.P.S. created the Vglut3-/- and VGLUT3 EGFP BAC transgenic mice; X.W. and R.P.S. performed behaviour and histology experiments; Y.G. performed in vivo spinal cord recordings; and C.J.W. and R.P.S. performed ex vivo recordings. R.H.E., R.P.S. and A.I.B. wrote the manuscript with contributions from C.J.W., Y.G., S.N.R. and X.W.

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Correspondence to Robert H. Edwards.

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Seal, R., Wang, X., Guan, Y. et al. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 462, 651–655 (2009). https://doi.org/10.1038/nature08505

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