Oncostatin M promotes chronic pain through direct regulation on nociceptors in rats

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Abstract
Oncostatin M (OSM), a member of the interleukin 6 (IL-6) pro-inflammatory cytokine family, is upregulated in the dorsal root ganglia of patients with neuropathic pain and thus may be an important contributor to this condition. Although suggested to contribute to itch in mice, the effects of OSM on nociceptive behavior and nociceptors in rats remain undefined. Here we show that a singular intrathecal dose of OSM (10 ng) induces significant mechanical hypersensitivity in both sexes of rats, yet does not alter thermal withdrawal latencies. When applied to cultured rat dorsal root ganglion (DRG) neurons, OSM (10 ng/mL) elicited robust action potential discharges and exaggerated fluctuations in membrane potential that was not mitigated by an IL-6 receptor antagonist. Neurons reactive to OSM typically did not respond to capsaicin, aligning with the behavioral observations. Immunohistochemical analysis revealed frequent co-localization of OSM and its receptor (OSMR) with isolectin B4–positive and calcitonin gene–related peptide–positive DRG neurons, but only scarce co-localization in transient receptor potential vanilloid 1–positive DRG neurons. In a model of paclitaxel chemotherapy–induced peripheral neuropathy, there is a notable increase in DRG neurons expressing OSM or its receptor (OSMR), alongside an upsurge in several OSM/OSMR downstream signaling molecules. These findings suggest that OSM acts as a signal for mechanical nociception and that heightened OSM expression and OSMR signaling in the DRG may be a key factor in the sensitization of specific nociceptor subsets. Consequently, targeting the OSM/OSMR pathway may offer a promising avenue for treatment in particular neuropathic pain phenotypes.
Funding Information
  • National Institute of Neurological Disorders and Stroke (NS111929)
  • National Institute of Neurological Disorders and Stroke (NS130608)
  • National Institute of Neurological Disorders and Stroke (NS132483)
  • National Institute of Neurological Disorders and Stroke (NS065926)
  • National Institute of Neurological Disorders and Stroke (NS111929)
  • National Institute of Neurological Disorders and Stroke (NS130608)
  • National Institute of Neurological Disorders and Stroke (NS065926)

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