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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.

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Change history

  • 03 December 2009

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

References

  1. Yoshimura, M. & Jessell, T. Amino acid-mediated EPSPs at primary afferent synapses with substantia gelatinosa neurones in the rat spinal cord. J. Physiol. (Lond.) 430, 315–335 (1990)

    Article  CAS  Google Scholar 

  2. Malmberg, A. B., Chen, C., Tonegawa, S. & Basbaum, A. I. Preserved acute pain and reduced neuropathic pain in mice lacking PKCγ. Science 278, 279–283 (1997)

    Article  CAS  Google Scholar 

  3. Fremeau, R. T., Voglmaier, S., Seal, R. P. & Edwards, R. H. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 27, 98–103 (2004)

    Article  CAS  Google Scholar 

  4. Bessou, P. & Perl, E. R. Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli. J. Neurophysiol. 32, 1025–1043 (1969)

    Article  CAS  Google Scholar 

  5. Iggo, A. & Kornhuber, H. H. A quantitative analysis of non-myelinated cutaneous mechano-receptors. J. Physiol. 198, 113passim (1968)

    CAS  PubMed  Google Scholar 

  6. Gras, C. et al. A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons. J. Neurosci. 22, 5442–5451 (2002)

    Article  CAS  Google Scholar 

  7. Todd, A. J. et al. The expression of vesicular glutamate transporters VGLUT1 and VGLUT2 in neurochemically defined axonal populations in the rat spinal cord with emphasis on the dorsal horn. Eur. J. Neurosci. 17, 13–27 (2003)

    Article  CAS  Google Scholar 

  8. Li, J. L., Fujiyama, F., Kaneko, T. & Mizuno, N. Expression of vesicular glutamate transporters, VGluT1 and VGluT2, in axon terminals of nociceptive primary afferent fibers in the superficial layers of the medullary and spinal dorsal horns of the rat. J. Comp. Neurol. 457, 236–249 (2003)

    Article  CAS  Google Scholar 

  9. Snider, W. D. & McMahon, S. B. Tackling pain at the source: new ideas about nociceptors. Neuron 20, 629–632 (1998)

    Article  CAS  Google Scholar 

  10. Seal, R. P. et al. Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron 57, 263–275 (2008)

    Article  CAS  Google Scholar 

  11. Gras, C. et al. The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone. Nature Neurosci. 11, 292–300 (2008)

    Article  CAS  Google Scholar 

  12. McNamara, C. R. et al. TRPA1 mediates formalin-induced pain. Proc. Natl Acad. Sci. USA 104, 13525–13530 (2007)

    Article  ADS  CAS  Google Scholar 

  13. Chung, J. M., Kenshalo, D. R., Gerhart, K. D. & Willis, W. D. Excitation of primate spinothalamic neurons by cutaneous C-fiber volleys. J. Neurophysiol. 42, 1354–1369 (1979)

    Article  CAS  Google Scholar 

  14. Kayser, V. & Guilbaud, G. Local and remote modifications of nociceptive sensitivity during carrageenin-induced inflammation in the rat. Pain 28, 99–107 (1987)

    Article  CAS  Google Scholar 

  15. Shields, S. D., Eckert, W. A. & Basbaum, A. I. Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis. J. Pain 4, 465–470 (2003)

    Article  Google Scholar 

  16. Brennan, T. J., Vandermeulen, E. P. & Gebhart, G. F. Characterization of a rat model of incisional pain. Pain 64, 493–502 (1996)

    Article  CAS  Google Scholar 

  17. Caterina, M. J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313 (2000)

    Article  ADS  CAS  Google Scholar 

  18. Treede, R. D., Meyer, R. A., Raja, S. N. & Campbell, J. N. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog. Neurobiol. 38, 397–421 (1992)

    Article  CAS  Google Scholar 

  19. Albers, K. M., Woodbury, C. J., Ritter, A. M., Davis, B. M. & Koerber, H. R. Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors. J. Neurosci. 26, 2981–2990 (2006)

    Article  CAS  Google Scholar 

  20. Liu, Q. et al. Molecular genetic visualization of a rare subset of unmyelinated sensory neurons that may detect gentle touch. Nature Neurosci. 10, 946–948 (2007)

    Article  CAS  Google Scholar 

  21. Christensen, B. N. & Perl, E. R. Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn. J. Neurophysiol. 33, 293–307 (1970)

    Article  CAS  Google Scholar 

  22. Schaible, H. G., Ebersberger, A. & Von Banchet, G. S. Mechanisms of pain in arthritis. Ann. NY Acad. Sci. 966, 343–354 (2002)

    Article  ADS  CAS  Google Scholar 

  23. Woolf, C. J. & Doubell, T. P. The pathophysiology of chronic pain–increased sensitivity to low threshold A beta-fibre inputs. Curr. Opin. Neurobiol. 4, 525–534 (1994)

    Article  CAS  Google Scholar 

  24. Neumann, S., Doubell, T. P., Leslie, T. & Woolf, C. J. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature 384, 360–364 (1996)

    Article  ADS  CAS  Google Scholar 

  25. Light, A. R., Trevino, D. L. & Perl, E. R. Morphological features of functionally defined neurons in the marginal zone and substantia gelatinosa of the spinal dorsal horn. J. Comp. Neurol. 186, 151–171 (1979)

    Article  CAS  Google Scholar 

  26. Boada, M. D. & Woodbury, C. J. Myelinated skin sensory neurons project extensively throughout adult mouse substantia gelatinosa. J. Neurosci. 28, 2006–2014 (2008)

    Article  CAS  Google Scholar 

  27. Neumann, S., Braz, J. M., Skinner, K., Llewellyn-Smith, I. J. & Basbaum, A. I. Innocuous, not noxious, input activates PKCγ interneurons of the spinal dorsal horn via myelinated afferent fibers. J. Neurosci. 28, 7936–7944 (2008)

    Article  CAS  Google Scholar 

  28. Abrahamsen, B. et al. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321, 702–705 (2008)

    Article  ADS  CAS  Google Scholar 

  29. Löken, L. S., Wessberg, J., Morrison, I., McGlone, F. & Olausson, H. Coding of pleasant touch by unmyelinated afferents in humans. Nature Neurosci. 12, 547–548 (2009)

    Article  Google Scholar 

  30. Yang, X. W., Model, P. & Heintz, N. Homologous recombination based modification in Escherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome. Nature Biotechnol. 15, 859–865 (1997)

    Article  CAS  Google Scholar 

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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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