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Proc Natl Acad Sci U S A. 2018 Aug 21;115(34):E8057-E8066. doi: 10.1073/pnas.1721815115. Epub 2018 Aug 6.

Macrophage angiotensin II type 2 receptor triggers neuropathic pain.

Author information

1
Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110; a.shepherd@wustl.edu d.p.mohapatra@wustl.edu.
2
Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242.
3
Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110.
4
Center for the Study of Itch, Department of Dermatology, Washington University School of Medicine, St. Louis, MO 63110.
5
Division of Nephrology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.
6
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
7
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610.
8
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110.
9
Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110.

Abstract

Peripheral nerve damage initiates a complex series of structural and cellular processes that culminate in chronic neuropathic pain. The recent success of a type 2 angiotensin II (Ang II) receptor (AT2R) antagonist in a phase II clinical trial for the treatment of postherpetic neuralgia suggests angiotensin signaling is involved in neuropathic pain. However, transcriptome analysis indicates a lack of AT2R gene (Agtr2) expression in human and rodent sensory ganglia, raising questions regarding the tissue/cell target underlying the analgesic effect of AT2R antagonism. We show that selective antagonism of AT2R attenuates neuropathic but not inflammatory mechanical and cold pain hypersensitivity behaviors in mice. Agtr2-expressing macrophages (MΦs) constitute the predominant immune cells that infiltrate the site of nerve injury. Interestingly, neuropathic mechanical and cold pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs and AT2R-null hematopoietic cell transplantation. Our study identifies AT2R on peripheral MΦs as a critical trigger for pain sensitization at the site of nerve injury, and therefore proposes a translatable peripheral mechanism underlying chronic neuropathic pain.

KEYWORDS:

AT2R; angiotensin; chemogenetics; macrophage; neuropathic pain

PMID:
30082378
PMCID:
PMC6112686
[Available on 2019-02-21]
DOI:
10.1073/pnas.1721815115
[Indexed for MEDLINE]

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