A role for leucine-rich, glioma inactivated 1 in regulating pain sensitivity

Adham Farah; Ryan Patel; Piotr Poplawski; Benjamin J Wastie; Mandy Tseng; Allison M Barry; Omar Daifallah; Akash Dubb; Ivan Paul; Hoi Lao Cheng; Faisal Feroz; Yuhe Su; Marva Chan; Hanns Ulrich Zeilhofer; Theodore Price; David L Bennett; Kirsty Bannister; John M Dawes

doi:10.1093/brain/awae302

A role for leucine-rich, glioma inactivated 1 in regulating pain sensitivity

Brain. 2024 Sep 20:awae302. doi: 10.1093/brain/awae302. Online ahead of print.

Authors

Adham Farah¹, Ryan Patel², Piotr Poplawski¹, Benjamin J Wastie¹, Mandy Tseng¹, Allison M Barry³, Omar Daifallah¹, Akash Dubb¹, Ivan Paul¹, Hoi Lao Cheng¹, Faisal Feroz¹, Yuhe Su¹, Marva Chan¹, Hanns Ulrich Zeilhofer^{4

5}, Theodore Price³, David L Bennett¹, Kirsty Bannister², John M Dawes¹

Affiliations

¹ Nuffield Department of Clinical Neurosciences, University of Oxford, OX3 9DU, UK.
² Wolfson Sensory, Pain & Regeneration Centre, Guy's Campus, Kings College London, SE1 1 UL, UK.
³ Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, Department of Neuroscience, University of Texas at Dallas, Texas 75080, USA.
⁴ Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
⁵ Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.

PMID: 39301592
DOI: 10.1093/brain/awae302

Abstract

Neuronal hyperexcitability is a key driver of persistent pain states including neuropathic pain. Leucine-rich, glioma inactivated 1 (LGI1), is a secreted protein known to regulate excitability within the nervous system and is the target of autoantibodies from neuropathic pain patients. Therapies that block or reduce antibody levels are effective at relieving pain in these patients, suggesting that LGI1 has an important role in clinical pain. Here we have investigated the role of LGI1 in regulating neuronal excitability and pain-related sensitivity by studying the consequences of genetic ablation in specific neuron populations using transgenic mouse models. LGI1 has been well studied at the level of the brain, but its actions in the spinal cord and peripheral nervous system (PNS) are poorly understood. We show that LGI1 is highly expressed in DRG and spinal cord dorsal horn neurons in both mouse and human. Using transgenic muse models, we genetically ablated LGI1, either specifically in nociceptors (LGI1fl/Nav1.8+), or in both DRG and spinal neurons (LGI1fl/Hoxb8+). On acute pain assays, we find that loss of LGI1 resulted in mild thermal and mechanical pain-related hypersensitivity when compared to littermate controls. In from LGI1fl/Hoxb8+ mice, we find loss of Kv1 currents and hyperexcitability of DRG neurons. LGI1fl/Hoxb8+ mice displayed a significant increase in nocifensive behaviours in the second phase of the formalin test (not observed in LGI1fl/Nav1.8+ mice) and extracellular recordings in LGI1fl/Hoxb8+ mice revealed hyperexcitability in spinal dorsal horn neurons, including enhanced wind-up. Using the spared nerve injury model, we find that LGI1 expression is dysregulated in the spinal cord. LGI1fl/Nav1.8+ mice showed no differences in nerve injury induced mechanical hypersensitivity, brush-evoked allodynia or spontaneous pain behaviour compared to controls. However, LGI1fl/Hoxb8+ mice showed a significant exacerbation of mechanical hypersensitivity and allodynia. Our findings point to effects of LGI1 at both the level of the DRG and spinal cord, including an important impact of spinal LGI1 on pathological pain. Overall, we find a novel role for LGI1 with relevance to clinical pain.

Keywords: glioma inactivated 1 (LGI1); hyperexcitability; leucine-rich; mechanical pain-hypersensitivity; neuropathic pain; wind-up.