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J Neurosci. 2018 Aug 8;38(32):7032-7057. doi: 10.1523/JNEUROSCI.3542-17.2018. Epub 2018 Jul 5.

Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain.

Author information

1
Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, Missouri 63110.
2
Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
3
Danish Pain Research Center, Department of Clinical Medicine, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
4
Department of Clinical Medicine, Core Center for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
5
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida 32610.
6
Departments of Medicine, Pathology, and Immunology, Washington University School of Medicine, St. Louis, Missouri, 63110.
7
School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080.
8
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610.
9
Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri 63110, and.
10
Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, Missouri 63110, d.p.mohapatra@wustl.edu.
11
Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri 63110.

Abstract

Injury, inflammation, and nerve damage initiate a wide variety of cellular and molecular processes that culminate in hyperexcitation of sensory nerves, which underlies chronic inflammatory and neuropathic pain. Using behavioral readouts of pain hypersensitivity induced by angiotensin II (Ang II) injection into mouse hindpaws, our study shows that activation of the type 2 Ang II receptor (AT2R) and the cell-damage-sensing ion channel TRPA1 are required for peripheral mechanical pain sensitization induced by Ang II in male and female mice. However, we show that AT2R is not expressed in mouse and human dorsal root ganglia (DRG) sensory neurons. Instead, expression/activation of AT2R on peripheral/skin macrophages (MΦs) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs. Furthermore, AT2R activation in MΦs triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on mouse and human DRG sensory neurons via cysteine modification of the channel. Our study thus identifies a translatable immune cell-to-sensory neuron signaling crosstalk underlying peripheral nociceptor sensitization. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic pain and thus identifies multiple druggable analgesic targets.SIGNIFICANCE STATEMENT Pain is a widespread health problem that is undermanaged by currently available analgesics. Findings from a recent clinical trial on a type II angiotensin II receptor (AT2R) antagonist showed effective analgesia for neuropathic pain. AT2R antagonists have been shown to reduce neuropathy-, inflammation- and bone cancer-associated pain in rodents. We report that activation of AT2R in macrophages (MΦs) that infiltrate the site of injury, but not in sensory neurons, triggers an intercellular redox communication with sensory neurons via activation of the cell damage/pain-sensing ion channel TRPA1. This MΦ-to-sensory neuron crosstalk results in peripheral pain sensitization. Our findings provide an evidence-based mechanism underlying the analgesic action of AT2R antagonists, which could accelerate the development of efficacious non-opioid analgesic drugs for multiple pain conditions.

KEYWORDS:

AT2R; TRPA1; angiotensin II; neuroimmune interaction; oxidative stress; pain

PMID:
29976627
PMCID:
PMC6083458
[Available on 2019-02-08]
DOI:
10.1523/JNEUROSCI.3542-17.2018

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