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Papers of the Week

Papers: 10 Jul 2021 - 16 Jul 2021

Animal Studies

2021 Jul 08


Genetic and functional evidence for gp130/IL6ST-induced TRPA1 upregulation in uninjured but not injured neurons in a mouse model of neuropathic pain.



Peripheral nerve injuries result in pronounced alterations in dorsal root ganglia (DRG), which can lead to the development of neuropathic pain. Although the polymodal mechanosensitive transient receptor potential ankyrin 1 ion channel (TRPA1) is emerging as a relevant target for potential analgesic therapies, preclinical studies do not provide unequivocal mechanistic insight into its relevance for neuropathic pain pathogenesis. By utilizing a transgenic mouse model with a conditional depletion of the interleukin-6 signal transducer gp130 in Nav1.8 expressing neurons (SNS-gp130-/-), we provide a mechanistic regulatory link between IL-6/gp130 and TRPA1 in the spared nerve injury model (SNI). SNI mice developed profound mechanical hypersensitivity as indicated by increased responses in the von Frey behavioral test in vivo, as well as a significant increase in mechanosensitivity of unmyelinated nociceptive primary afferents in ex vivo skin nerve recordings. In contrast to wild type and control gp130fl/fl animals, SNS-gp130-/- mice did not develop mechanical hypersensitivity after SNI and exhibited low levels of Trpa1 mRNA in sensory neurons, which were partially restored by adenoviral gp130 re-expression in vitro. Importantly, uninjured but not injured neurons developed increased responsiveness to the TRPA1 agonist cinnamon aldehyde (CA), and neurons derived from SNS-gp130-/- mice after SNI were significantly less responsive to CA. Our study shows for the first time that TRPA1 upregulation is attributed specifically to uninjured neurons in the SNI model and this depended on the IL-6 signal transducer gp130. We provide a solution to the enigma of TRPA1 regulation following nerve injury and stress its significance as an important target for neuropathic pain disorders.