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

The Sigma-1 receptor (σ₁R) 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 σ₁R and σ₁R-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 σ₁R inhibition at a selected segmental level, we designed a recombinant adeno-associated viral (AAV) vector expressing a small hairpin RNA (shRNA) against rat σ₁R. Injection of this vector into the L4/L5 DRGs induced downregulation of σ₁R 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 σ₁R suppressed neuronal excitability, suggesting that σ₁R silencing attenuates pain by reversal of injury-induced neuronal hyperexcitability. These findings support a critical role of σ₁R in modulating PSN nociceptive functions, and that the nerve injury-induced elevated σ₁R activity in the PSNs can be a significant driver of neuropathic pain. Further understanding the role of PSN-σ₁R in pain pathology may open routes to exploit this system for DRG-targeted pain therapy.