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05 December 2018 : Animal Research  

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

Aitao Wang1ABCDEF, Tingting Yang2DEF, Lingli Zhang3EFG, Lizhou Jia2CE, Qingping Wu4AF, Shanglong Yao4BCD, Jianjun Xu5DFG, Hongxin Yang6ACDEG*

DOI: 10.12659/MSM.913787

Med Sci Monit 2018; 24: ANS8804-8811

Abstract

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

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750