puc-header

Defining a Spinal Microcircuit that Gates Myelinated Afferent Input: Implications for Tactile Allodynia

50 Pages Posted: 30 Apr 2019 Sneak Peek Status: Published

See all articles by Kieran A. Boyle

Kieran A. Boyle

University of Glasgow - Spinal Cord Research Group

Mark A. Gradwell

University of Newcastle (Australia) - School of Biomedical Sciences and Pharmacy

Toshiharu Yasaka

Saga University - Department of Anatomy and Physiology

Allen C. Dickie

University of Glasgow - Spinal Cord Research Group

Erika Polgár

University of Glasgow - Spinal Cord Research Group

Robert P. Ganley

University of Glasgow - Spinal Cord Research Group

Desmond PH Orr

University of Glasgow - Spinal Cord Research Group

Masahiko Watanabe

Hokkaido University - Department of Anatomy

Victoria E. Abraira

Harvard University - Department of Neurobiology

Emily D. Kuehn

Harvard University - Department of Neurobiology

Amanda L. Zimmermann

Harvard University - Department of Neurobiology

David D. Ginty

Harvard University - Department of Neurobiology

Robert J. Callister

University of Newcastle (Australia) - School of Biomedical Sciences and Pharmacy

Brett A. Graham

University of Newcastle (Australia) - School of Biomedical Sciences and Pharmacy

David I. Hughes

University of Glasgow - Spinal Cord Research Group

More...

Abstract

Chronic pain presents a major unmet clinical problem. One of the most common symptoms of chronic pain is tactile allodynia, where previously innocuous mechanical stimuli are perceived as painful. To help develop more effective analgesics to treat this condition, a better understanding of the neuronal circuits underlying sensory perception in necessary. We have shown that inhibitory interneurons in the spinal dorsal horn that express parvalbumin (PV) form axoaxonic synapses on to the central terminals of low threshold mechanoreceptive (LTMR) afferents. Here, we define a spinal microcircuit comprising of LTMR afferents, inhibitory PV interneurons, and glutamatergic vertical cells whose axons project to lamina I, that explains how LTMR input can activate pain circuits under pathological conditions. We show that these PV cells receive monosynaptic input from myelinated LTMR afferents from both hairy and glabrous skin. We also determine that these interneurons are the source of axoaxonic synapses on to the central terminals of LTMR afferents that appose vertical cells, forming triadic synaptic arrangements. Furthermore, we provide evidence that these interneurons generate both GABAergic presynaptic inhibition of myelinated LTMR afferents, and postsynaptic inhibition of vertical cells through the release of GABA and glycine. In neuropathic mice, PV cell excitability is reduced, but we find no evidence of structural plasticity. Taken together, these findings show that PV cell-mediated presynaptic inhibition of LTMR afferents and postsynaptic inhibition of vertical cells both play critical roles in the normal perception of mechanical stimuli, and identify this microcircuit as a target for therapeutic intervention to alleviate allodynia.

Keywords: Touch, Allodynia, Presynaptic inhibition, Interneurons, LTMRs

Suggested Citation

Boyle, Kieran A. and Gradwell, Mark A. and Yasaka, Toshiharu and Dickie, Allen C. and Polgár, Erika and Ganley, Robert P. and Orr, Desmond PH and Watanabe, Masahiko and Abraira, Victoria E. and Kuehn, Emily D. and Zimmermann, Amanda L. and Ginty, David D. and Callister, Robert J. and Graham, Brett A. and Hughes, David I., Defining a Spinal Microcircuit that Gates Myelinated Afferent Input: Implications for Tactile Allodynia (April 24, 2019). CELL-REPORTS-D-19-01218. Available at SSRN: https://ssrn.com/abstract=3377640 or http://dx.doi.org/10.2139/ssrn.3377640
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Kieran A. Boyle

University of Glasgow - Spinal Cord Research Group ( email )

United Kingdom

Mark A. Gradwell

University of Newcastle (Australia) - School of Biomedical Sciences and Pharmacy ( email )

Australia

Toshiharu Yasaka

Saga University - Department of Anatomy and Physiology ( email )

Japan

Allen C. Dickie

University of Glasgow - Spinal Cord Research Group ( email )

United Kingdom

Erika Polgár

University of Glasgow - Spinal Cord Research Group ( email )

United Kingdom

Robert P. Ganley

University of Glasgow - Spinal Cord Research Group ( email )

United Kingdom

Desmond PH Orr

University of Glasgow - Spinal Cord Research Group ( email )

United Kingdom

Masahiko Watanabe

Hokkaido University - Department of Anatomy

Sapporo, Hokkaido 060-0809
Japan

Victoria E. Abraira

Harvard University - Department of Neurobiology ( email )

United States

Emily D. Kuehn

Harvard University - Department of Neurobiology ( email )

United States

Amanda L. Zimmermann

Harvard University - Department of Neurobiology ( email )

United States

David D. Ginty

Harvard University - Department of Neurobiology ( email )

United States

Robert J. Callister

University of Newcastle (Australia) - School of Biomedical Sciences and Pharmacy ( email )

Australia

Brett A. Graham (Contact Author)

University of Newcastle (Australia) - School of Biomedical Sciences and Pharmacy ( email )

Australia

David I. Hughes

University of Glasgow - Spinal Cord Research Group ( email )

United Kingdom

Click here to go to Cell.com

Go to Cell.com

Paper statistics

Abstract Views
149
Downloads
4