A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior
- 11 January 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (3)
- https://doi.org/10.1073/pnas.2021220118
Abstract
A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP+) and show that specific ablation or silencing of AAV-NpyP+ SDH interneurons converted touch-sensing Aβ fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP+ neurons received excitatory inputs from Aβ fibers and transmitted inhibitory GABA signals to lamina I neurons projecting to the brain. In a model of neuropathic pain developed by peripheral nerve injury, AAV-NpyP+ neurons exhibited deeper resting membrane potentials, and their excitation by Aβ fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP+ neurons in nerve-injured rats reversed Aβ fiber-derived neuropathic pain-like behavior that was shown to be morphine-resistant and reduced pathological neuronal activation of superficial SDH including lamina I. These findings suggest that identified inhibitory SDH interneurons that act as a critical brake on conversion of touch-sensing Aβ fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.Keywords
This publication has 53 references indexed in Scilit:
- New approach for investigating neuropathic allodynia by optogeneticsPain, 2019
- Uncovering the Cells and Circuits of Touch in Normal and Pathological SettingsNeuron, 2018
- Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neuronsNature Communications, 2018
- Spinal Circuits Transmitting Mechanical Pain and ItchNeuroscience Bulletin, 2017
- Neuropathic painNature Reviews Disease Primers, 2017
- Erratum: Structural plasticity and reorganisation in chronic painNature Reviews Neuroscience, 2017
- Neural circuits for pain: Recent advances and current viewsScience, 2016
- Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockadeNature Medicine, 2015
- The Low-Threshold Calcium Channel Cav3.2 Determines Low-Threshold Mechanoreceptor FunctionCell Reports, 2015
- VGluT3+Primary Afferents Play Distinct Roles in Mechanical and Cold Hypersensitivity Depending on Pain EtiologyJournal of Neuroscience, 2014