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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.

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


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.


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


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