Open AccessSigma-1 receptor activity in primary sensory neurons is a critical driver of neuropathic pain
Author(s) -
Seung-Soo Shin,
Fei Wang,
Chensheng Qiu,
Brandon Itson-Zoske,
Quinn H. Hogan,
Hongwei Yu
Publication year - 2020
Publication title -
gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.332
H-Index - 159
eISSN - 1476-5462
pISSN - 0969-7128
DOI - 10.1038/s41434-020-0157-5
Subject(s) - neuropathic pain , sni , nerve injury , small hairpin rna , nociception , medicine , neuroscience , gene knockdown , sigma 1 receptor , dorsal root ganglion , gene silencing , receptor , sensory system , anesthesia , biology , cell culture , agonist , gene , biochemistry , genetics , hydrolysis , acid hydrolysis
The Sigma-1 receptor (σ 1 R) 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 σ 1 R and σ 1 R-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 σ 1 R inhibition at a selected segmental level, we designed a recombinant adeno-associated viral (AAV) vector expressing a small hairpin RNA (shRNA) against rat σ 1 R. Injection of this vector into the L4/L5 DRGs induced downregulation of σ 1 R 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 σ 1 R suppressed neuronal excitability, suggesting that σ 1 R silencing attenuates pain by reversal of injury-induced neuronal hyperexcitability. These findings support a critical role of σ 1 R in modulating PSN nociceptive functions, and that the nerve injury-induced elevated σ 1 R activity in the PSNs can be a significant driver of neuropathic pain. Further understanding the role of PSN-σ 1 R in pain pathology may open routes to exploit this system for DRG-targeted pain therapy.