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

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 phenotypeNeurofarmacología del dolor de la Universidad de Granada (CTS-109)FPU grants from the Spanish Ministry of Education, Culture and Sports.Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2016-80540-R)the Junta de Andalucía (grant CTS 109)Esteve PharmaceuticalsEuropean Regional Development Fund (ERDF