Direct Effects of the Janus Kinase Inhibitor Baricitinib on Sensory Neurons

Area of Science:

• Neuroscience
• Pharmacology
• Immunology

Background:

• Rheumatoid arthritis is associated with pain, and baricitinib is a Janus kinase (JAK) inhibitor used therapeutically.
• The direct impact of baricitinib on joint nociceptors and pain signaling remains to be fully elucidated.

Purpose of the Study:

• To investigate the direct effects of baricitinib on nociceptive C- and A∂-fibers in normal and inflamed rat knee joints.
• To determine if baricitinib modulates neuronal excitability and signaling pathways involved in inflammatory pain.

Main Methods:

• Electrophysiological recordings of C- and A∂-fibers in anesthetized rats responding to joint rotation.
• Western blot analysis of Stat3 activation and patch-clamp recordings of dorsal root ganglion (DRG) neurons in vitro.
• Intra-articular administration of baricitinib and assessment of responses to inflammatory mediators like IL-6, sIL-6R, and TNF.

Main Results:

• Baricitinib reduced C-fiber responses to noxious stimuli in inflamed joints but not in normal joints.
• Baricitinib inhibited IL-6/sIL-6R-induced C-fiber hyperexcitability but not TNF-induced responses.
• Baricitinib blocked Stat3 activation by IL-6 and prevented IL-6/sIL-6R-induced hyperexcitability in DRG neurons.

Conclusions:

• Neuronal JAKs play a role in inflammation-induced C-fiber hyperexcitability, particularly through IL-6 signaling.
• Baricitinib's pain-reducing effects in rheumatoid arthritis may stem partly from its direct action on joint nociceptors.
• Targeting neuronal JAK-STAT pathways offers a potential strategy for managing inflammatory pain.