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

The Sigma-1 receptor (sigma R-1) 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 sigma R-1 and sigma R-1-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 sigma R-1 inhibition at a selected segmental level, we designed a recombinant adeno-associated viral (AAV) vector expressing a small hairpin RNA (shRNA) against rat sigma R-1. Injection of this vector into the L4/L5 DRGs induced downregulation of sigma R-1 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 sigma R-1 suppressed neuronal excitability, suggesting that sigma R-1 silencing attenuates pain by reversal of injury-induced neuronal hyperexcitability. These findings support a critical role of sigma R-1 in modulating PSN nociceptive functions, and that the nerve injury-induced elevated sigma R-1 activity in the PSNs can be a significant driver of neuropathic pain. Further understanding the role of PSN-sigma R-1 in pain pathology may open routes to exploit this system for DRG-targeted pain therapy.