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Neuronal allodynic mechanisms of Slc7a5 (LAT1) in the spared nerve injury rodent model of neuropathic pain

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Abstract

High-impact chronic pain is suffered by 1 in 5 patients in the USA and globally. Effective, non-addictive, non-opioid therapeutics are urgently needed for the treatment of chronic pain. Slc7a5 (Lat1), also known as system L-neutral amino acid transporter, is involved in a number of physiological processes related to inflammation. Transcriptomics studies have shown that Slc7a5 and its binding partner Slc3a2 are expressed in neurons of the dorsal root ganglia (DRG) and spinal dorsal horn, which are critical to the initiation and maintenance of nociception and pathophysiology of chronic pain. In addition, Slc7a5 is a transporter for the first-line anti-allodynic gabapentinoid drugs and binds to ion channels implicated in nociception and chronic pain including the voltage-gated sodium channel Nav1.7 and the voltage-gated potassium channels Kv1.1 and Kv1.2. We found that blocking Slc7a5 with intrathecal administration of the drug JPH203 alleviated allodynia in the spared nerve injury (SNI) rodent model of neuropathic pain. Western blot and immunohistochemistry studies revealed an increase in Slc7a5 protein levels in the spinal cord and DRGs of SNI mice compared to control mice. Using whole-cell current-clamp electrophysiology, we observed that JPH203 treatment reduced excitability of small-diameter (< 30 µm) DRG neurons from SNI mice, in agreement with its behavioral effects. Voltage-clamp recordings from JPH203-treated naïve rat DRGs identified an effect on tetrodotoxin-resistant (TTX-R) sodium currents. Altogether, these results demonstrate that Slc7a5 is dysregulated in chronic neuropathic pain and can be targeted to provide relief of hypersensitivity.

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Acknowledgements

We thank Prof. Karin N. Westlund and Dr. Sabrina McIlwrath for assistance with immunohistochemistry experiments. We thank Marena Montera for assistance with western blot experiments and lab management.

Funding

S.R.A.A received funding from the Research Endowment Fund of the Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of Medicine. Supported by National Institutes of Health awards (NINDS (NS098772 and NS120663 to RK).

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Authors and Affiliations

  1. Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of Medicine, Albuquerque, NM, 87106, USA

    Aleyah E. Goins, Mitra Afaghpour-Becklund & Sascha R. A. Alles

  2. Comprehensive Pain and Addiction Center, The University of Arizona, Tucson, AZ, 85724, USA

    Kimberly Gomez, Dongzhi Ran & Rajesh Khanna

  3. Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, 85724, USA

    Kimberly Gomez, Dongzhi Ran & Rajesh Khanna

  4. Department of Molecular Pathobiology, College of Dentistry, New York University, 133 First Avenue Rm 824, New York, NY, 10010, USA

    Rajesh Khanna

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  1. Aleyah E. Goins
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  2. Kimberly Gomez
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  3. Dongzhi Ran
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  4. Mitra Afaghpour-Becklund
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  6. Sascha R. A. Alles
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Correspondence to Rajesh Khanna or Sascha R. A. Alles.

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Conflict of interest

R. Khanna is the co-founder of Regulonix LLC, a company developing non-opioids drugs for chronic pain. In addition, R. Khanna 481 has patents US10287334 (Non-narcotic CRMP2 peptides targeting sodium channels for chronic 482 pain) and US10441586 (SUMOylation inhibitors and uses thereof) issued to Regulonix LLC. R. Khanna is also a co-founder of ElutheriaTx Inc., a company developing gene therapy approaches for chronic pain.

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This article is part of the special issue on Nociception in Pflügers Archiv—European Journal of Physiology

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Goins, A.E., Gomez, K., Ran, D. et al. Neuronal allodynic mechanisms of Slc7a5 (LAT1) in the spared nerve injury rodent model of neuropathic pain. Pflugers Arch - Eur J Physiol 474, 397–403 (2022). https://doi.org/10.1007/s00424-021-02653-9

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  • DOI: https://doi.org/10.1007/s00424-021-02653-9

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