Fractalkine Signaling in Microglia Contributes to Ectopic Orofacial Pain following Trapezius Muscle Inflammation

Abstract

Fractalkine (FKN) signaling is involved in mechanical allodynia in the facial skin following trapezius muscle inflammation. Complete Freund's adjuvant (CFA) injection into the trapezius muscle produced mechanical allodynia in the ipsilateral facial skin that was not associated with facial skin inflammation and resulted in FKN but not FKN receptor (CX3CR1) expression, and microglial activation was enhanced in trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). Intracisterna magna anti-CX3CR1 or anti-interleukin (IL)-1␤ neutralizing antibody administration decreased the enhanced excitability of Vc and C1-C2 neurons in CFA-injected rats, whereas intra-cisterna magna FKN administration induced microglial activation and mechanical allodynia in the facial skin. IL-1␤ expression and p38 mitogen-activated protein kinase phosphorylation were enhanced in activated microglia after CFA injection. The excitability of neurons whose receptive fields was located in the facial skin was significantly enhanced in CFA-injected rats, and the number of cells expressing phosphorylated extracellular signal-regulated kinase (pERK) following noxious mechanical stimulation of the facial skin was significantly increased in Vc and C1-C2. We also observed mechanical allodynia of the trapezius muscle as well as microglial activation and increased pERK expression in C2-C6 after noxious stimulation of the trapezius muscle in facial skin-inflamed rats. These findings suggest that FKN expression was enhanced in Vc and C1-C2 or C2-C6 following trapezius muscle or facial skin inflammation, microglia are activated via FKN signaling, IL-1␤ is released from the activated microglia, and the excitability of neurons in Vc and C1-C2 or C2-C6 is enhanced, resulting in the ectopic mechanical allodynia.

CX3CR1 ablation ameliorates motor and respiratory dysfunctions and improves survival of a Rett syndrome mouse model

“…To our knowledge, our report is the first to address the significance of CX 3 CL1–CX 3 CR1 signaling in a childhood neurodevelopmental disorder devoid of a clear component of neuroinflammation, and suggests a novel therapeutic approach for RTT by targeting CX 3 CR1 with specific antagonists or genetic downregulation. Various “anti-CX 3 CR1” approaches, such as neutralizing antibodies against CX 3 -CR1, small molecule and peptide inhibitors, and CX 3 CR1 siRNA, have been tested in models of other disorders and could have potential therapeutic utilities for RTT (Kiyomoto et al, 2013; Poupel et al, 2013; Wu et al, 2013; Ridderstad Wollberg et al, 2014). Moreover, RTT is highly relevant to our understanding of autism, a group of high-prevalence developmental disorders.…”

Hyperexcitability in Spinal WDR Neurons following Experimental Disc Herniation Is Associated with Upregulation of Fractalkine and Its Receptor in Nucleus Pulposus and the Dorsal Root Ganglion

“…Therefore, it seems likely that persistent hyperexcitability in the pain pathways after disc herniation is associated with a local inflammatory process including activation of macrophages close to the nerve roots. Moreover, previous data show that IL-1 β [24, 25], Csf1 [26–28], and CX3CL1 [22, 29, 30] can induce M1 microglia activation. For the first time, however, we showed that application of NP onto the dorsal nerve roots also increased the gene expression of CX3CL1 and CX3CR1 in the NP cells and in the ipsilateral DRGs.…”

Neuron-glia interaction is a key mechanism underlying persistent orofacial pain

“…Activated microglial cells change their morphological features, e.g., shrinking of processes or soma swelling (23). Activated microglial cells express phosphorylated p38 and release various molecules (such as brain-derived neurotrophic factor [BDNF]) and cytokines after inflammation and tumor necrosis factor, cytokines, BDNF, ATP, prostaglandin, and nitric oxide after trigeminal nerve injury (24)(25)(26). These molecules bind their receptors, and the excitability of Vc and C1-C2 neurons is modulated.…”