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FASEB J. 2020 Apr;34(4):5951-5966. doi: 10.1096/fj.201901921R. Epub 2020 Mar 10.

Sigma-1 receptors control neuropathic pain and macrophage infiltration into the dorsal root ganglion after peripheral nerve injury.

Author information

1
Department of Pharmacology, School of Medicine, University of Granada, Granada, Spain.
2
Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain.
3
Instituto de Investigación Biosanitaria IBS. GRANADA, Granada, Spain.
4
Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada, Spain.
5
Institute of Molecular Biotechnology, Vienna, Austria.
6
Drug Discovery and Preclinical Development, Esteve, Barcelona, Spain.
7
Department of Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt.
8
Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, Canada.
9
Teófilo Hernando Institute for Drug Discovery, Madrid, Spain.

Abstract

Neuron-immune interaction in the dorsal root ganglia (DRG) plays a pivotal role in the neuropathic pain development after nerve injury. Sigma-1 receptor (Sig-1R) is expressed by DRG neurons but its role in neuropathic pain is not fully understood. We investigated the effect of peripheral Sig-1R on neuroinflammation in the DRG after spared (sciatic) nerve injury (SNI) in mice. Nerve injury induced a decrease in NeuN staining along with the nuclear eccentricity and ATF3 expression in the injured DRG. Sig-1R was present in all DRG neurons examined, and after SNI this receptor translocated to the periphery of the soma and the vicinity of the nucleus, especially in injured ATF3 + neurons. In WT mice, injured DRG produced the chemokine CCL2, and this was followed by massive infiltration of macrophages/monocytes, which clustered mainly around sensory neurons with translocated Sig-1R, accompanied by robust IL-6 increase and mechanical allodynia. In contrast, Sig-1R knockout (Sig-1R-KO) mice showed reduced levels of CCL2, decreased macrophage/monocyte infiltration into DRG, and less IL-6 and neuropathic mechanical allodynia after SNI. Our findings point to an important role of peripheral Sig-1R in sensory neuron-macrophage/monocyte communication in the DRG after peripheral nerve injury; thus, these receptors may contribute to the neuropathic pain phenotype.

KEYWORDS:

ATF3; CCL2; IL-6; neuroinflammation; spared nerve injury

PMID:
32157739
DOI:
10.1096/fj.201901921R

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