Fractalkine/CX3CR1 signaling during neuropathic pain

Abstract

Chronic pain represents a major problem in clinical medicine. Whilst the acute pain that is associated with tissue injury is a protective signal that serves to maintain homeostasis, chronic pain is a debilitating condition that persists long after the inciting stimulus subsides. Chronic neuropathic pain that develops following damage or disease of the nervous system is partially treated by current therapies, leaving scope for new therapies to improve treatment outcome. Peripheral nerve damage is associated with alterations to the sensory neuroaxis that promote maladaptive augmentation of nociceptive transmission. Thus, neuropathic pain patients exhibit exaggerated responses to noxious stimuli, as well as pain caused by stimuli which are normally non-painful. Increased nociceptive input from the periphery triggers physiological plasticity and long lasting transcriptional and post-translational changes in the CNS defined as central sensitization. Nerve injury induces gliosis which contributes to central sensitization and results in enhanced communication between neurons and microglial cells within the dorsal horn. Thus, identification of mechanisms regulating neuro-immune interactions that occur during neuropathic pain may provide future therapeutic targets. Specifically, chemokines and their receptors play a pivotal role in mediating neuro-immune communication which leads to increased nociception. In particular, the chemokine Fractalkine (FKN) and the CX3CR1 receptor have come to light as a key signaling pair during neuropathic pain states.

Keywords: chemokines; chronic pain; microglia; pain; proteases.

Figure 1

Schematic illustrating the pro-nociceptive mechanism of CatS/FKN signaling in the spinal dorsal horn during neuropathic pain. (A–B) In the dorsal horn area innervated by damaged fibers (Panel A) microglia transform from a surveillance state into a reactive state following exposure to injury induced factors released by primary afferent terminals, including Adenosine tri-phosphate (ATP; Panel B). (C) High concentrations of extracellular ATP leads to P2X7 receptor activation on microglia (1), which ultimately leads to the release of CatS. A decrease in intracellular potassium concentration following efflux through the P2X7 receptor activates phospholipase C (PLC), resulting in an increase in intracellular calcium and phosphorylation of p38 MAPK. P38 phosphorylation then allows phospholipase A₂ (PLA₂) mediated translocation of CatS containing lysosomes to the cell membrane, whereby exocytosis releases CatS into the extracellular space (2). Extracellular CatS is then able to cleave membrane bound FKN from dorsal horn neurons, liberating soluble FKN (sFKN) (3). (D) sFKN feeds back onto the microglial cells via the CX3CR1 receptor (4) to further activate the p38 MAPK pathway and release inflammatory mediators, (5) that activate neurons and result in chronic pain. Abbreviations: DRG, dorsal root ganglia, cPLA₂, cytosolic PLA₂.