THE CHEMOKINE CXCL16 MODULATES NOCICEPTION BY REDUCING GABAERGIC INHIBITION VIA A GLIA-DEPENDENT PATHWAY

Tissue and nerve injury or disease often lead to chronic pain states that are difficult to treat and involve complex mechanisms including neuroimmune interactions. Chemokine CXCL16 has recently emerged as a potential modulator of pain signaling. The aim of this study was to elucidate the role of CXCL16 in nociceptive modulation using multimodal experimental approach combining in vitro and in vivo methods in several experimental pain models.
Behavioral experiments, calcium imaging in dorsal root ganglia neuronal (DRG) cultures, electrophysiological recording in spinal cord slices and molecular analysis using qPCR and ELISA were performed. Wistar rats and mice were used.
CXCL16 expression was significantly upregulated in DRG neurons and spinal cord dorsal horn in models of nerve injury and peripheral inflammation. Intrathecal application of exogenous CXCL16 induced mechanical and thermal hypersensitivity lasting over four days. CXCL16 enhanced neuronal excitability of DRG neurons and reduced GABAergic induced inhibition in a subset of neurons. These effects were prevented by minocycline, suggesting a glial cells activation-dependent mechanism.
All together our findings demonstrated that CXCL16 is upregulated under pathological conditions and suggested that it may serve as a key mediator of neuroinflammatory processes that modulate inhibitory GABAergic signaling. Modulation of the CXCL16 pathway may thus represent a novel therapeutic strategy for controlling painful states involving neuroimmune mechanisms.
This work was supported by the Grant Agency of the Czech Republic (24-10712S).