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IP3-Mediated Calcium Signaling Is Involved in the Mechanism of Fractalkine-Induced Hyperalgesia Response

Aitao Wang, Tingting Yang, Lingli Zhang, Lizhou Jia, Qingping Wu, Shanglong Yao, Jianjun Xu, Hongxin Yang

Department of Anesthesiology, Inner Mongolia Autonomous Region People’s Hospital, Hohhot, Inner Mongolia, China (mainland)

Med Sci Monit 2018; 24:8804-8811

DOI: 10.12659/MSM.913787

Available online:

Published: 2018-12-05

BACKGROUND: Fractalkine is widely expressed throughout the brain and spinal cord, where it can exert effects on pain enhancement and hyperalgesia by activating microglia through CX3C chemokine receptor 1 (CX3CR1), which triggers the release of several pro-inflammatory cytokines in the spinal cord. Fractalkine has also been shown to increase cytosolic calcium ([Ca2+]i) in microglia.
MATERIAL AND METHODS: Based on the characteristics of CX3CR1, a G protein-coupled receptor, we explored the role of inositol 1,4,5-trisphosphate (IP3) signaling in fractalkine-induced inflammatory response in BV-2 cells in vitro. The effect and the underlying mechanism induced by fractalkine in the brain were observed using a mouse model with intracerebroventricular (i.c.v.) injection of exogenous fractalkine.
RESULTS: [Ca2+]i was significantly increased and IL-1β and TNF-α levels were higher in the fractalkine-treated cell groups than in the farctalkine+ 2-APB groups. We found that i.c.v. injection of fractalkine significantly increased p-p38MAPK, IL-1β, and TNF-α expression in the brain, while i.c.v. injection of a fractalkine-neutralizing antibody (anti-CX3CR1), trisphosphate receptor (IP3R) antagonist (2-APB), or p38MAPK inhibitor (SB203580) prior to fractalkine addition yielded an effective and reliable anti-allodynia effect, following the reduction of p-p38MAPK, IL-1β, and TNF-α expression.
CONCLUSIONS: Our results suggest that fractalkine leads to hyperalgesia, and the underlying mechanism may be associated with IP3/p38MAPK-mediated calcium signaling and its phlogogenic properties.

Keywords: Chemokine CX3CL1, Hyperalgesia, Inositol 1,4,5-Trisphosphate, Mitogen-Activated Protein Kinase Kinases