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Papers of the Week

Papers: 16 May 2020 - 22 May 2020

Animal Studies

2020 May 18

Gene Ther

Sigma-1 receptor activity in primary sensory neurons is a critical driver of neuropathic pain.


Shin S M, Wang F, Qiu C, Itson-Zoske B, Hogan QH, Yu H
Gene Ther. 2020 May 18.
PMID: 32424233.


The Sigma-1 receptor (σR) is highly expressed in the primary sensory neurons (PSNs) that are the critical site of initiation and maintenance of pain following peripheral nerve injury. By immunoblot and immunohistochemistry, we observed increased expression of both σR and σR-binding immunoglobulin protein (BiP) in the lumbar (L) dorsal root ganglia (DRG) ipsilateral to painful neuropathy induced by spared nerve injury (SNI). To evaluate the therapeutic potential of PSN-targeted σR inhibition at a selected segmental level, we designed a recombinant adeno-associated viral (AAV) vector expressing a small hairpin RNA (shRNA) against rat σR. Injection of this vector into the L4/L5 DRGs induced downregulation of σR in DRG neurons of all size groups, while expression of BiP was not affected. This was accompanied by attenuation of SNI-induced cutaneous mechanical and thermal hypersensitivity. Whole-cell current-clamp recordings of dissociated neurons showed that knockdown of σR suppressed neuronal excitability, suggesting that σR silencing attenuates pain by reversal of injury-induced neuronal hyperexcitability. These findings support a critical role of σR in modulating PSN nociceptive functions, and that the nerve injury-induced elevated σR activity in the PSNs can be a significant driver of neuropathic pain. Further understanding the role of PSN-σR in pain pathology may open routes to exploit this system for DRG-targeted pain therapy.