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

Gene Therapy volume 29, pages 1–15 (2022)Cite this article

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Abstract

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.

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Fig. 1: IHC characterization of σ1R and BiP expression in DRG and SC of naïve rat.
Fig. 2: Increased σ1R and BiP levels in DRG following SNI.
Fig. 3: Efficient knockdown of σ1R by DRG injection of AAV6-σ1RsiRNA.
Fig. 4: Attenuation of SNI-induced pain behavior by AAV6σ1RsiRNA-mediated PSN-σ1R inhibition.
Fig. 5: Current-clamp analysis of AAV6σ1RsiRNA transduction on DRG neuron excitability.

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Acknowledgements

This research was supported by a grant from the Department of Veterans Affairs Rehabilitation Research and Development I01RX001940 (to QHH). The authors would like to thank Dr Tsung-Ping Su (IRP/NIDA/NIH) for providing plasmids encoding σ1R-shRNA and scramble RNA.

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Author notes

  1. These authors contributed equally: Seung Min Shin, Fei Wang

Authors and Affiliations

  1. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Seung Min Shin, Fei Wang, Chensheng Qiu, Brandon Itson-Zoske, Quinn H. Hogan & Hongwei Yu

  2. Zablocki Veterans Affairs Medical Center, Milwaukee, WI, 53295, USA

    Seung Min Shin, Quinn H. Hogan & Hongwei Yu

  3. Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang, 712046, Shaanxi, PR China

    Fei Wang

  4. Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, PR China

    Chensheng Qiu

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Shin, S.M., Wang, F., Qiu, C. et al. Sigma-1 receptor activity in primary sensory neurons is a critical driver of neuropathic pain. Gene Ther 29, 1–15 (2022). https://doi.org/10.1038/s41434-020-0157-5

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