Fractalkine/CX3CR1 Pathway in Neuropathic Pain: An Update

Abstract

Injuries to the nervous system can result in a debilitating neuropathic pain state that is often resistant to treatment with available analgesics, which are commonly associated with several side-effects. Growing pre-clinical and clinical evidence over the last two decades indicates that immune cell-mediated mechanisms both in the periphery and in the Central Nervous System (CNS) play significant roles in the establishment and maintenance of neuropathic pain. Specifically, following peripheral nerve injury, microglia, which are CNS resident immune cells, respond to the activity of the first pain synapse in the dorsal horn of spinal cord and also to neuronal activity in higher centres in the brain. This microglial response leads to the production and release of several proinflammatory mediators which contribute to neuronal sensitisation under neuropathic pain states. In this review, we collect evidence demonstrating the critical role played by the Fractalkine/CX3CR1 signalling pathway in neuron-to-microglia communication in neuropathic pain states and explore how strategies that include components of this pathway offer opportunities for innovative targets for neuropathic pain.

Inflammation and Interferon Signatures in Peripheral B-Lymphocytes and Sera of Individuals With Fibromyalgia

“…In addition to their role in the control and recruitment of effector leukocytes during infection, inflammation, tissue injury and tumour growth, chemokines are implicated in synaptic transmission and increase the sensitivity to pain by direct action on chemokine receptors expressed in peripheral nerves, the dorsal ganglia and in the spinal cord ( 62 , 63 ). There are now emerging evidences suggesting that altered chemokine levels may account for the central sensitization in FM patients and in other chronic pain conditions ( 64 , 65 ).…”

Effects of Olfactory Mucosa Stem/Stromal Cell and Olfactory Ensheating Cells Secretome on Peripheral Nerve Regeneration

“…Simultaneously, some anti-inflammatory cytokines such as IL-10 are also upregulated at this stage, probably contributing to the balance in the immune response and preventing deleterious inflammatory reactions [ 41 ]. Fractalkine participates in a signaling pathway in neuron-to-microglia communication and is related to the development of neuropathic pain phenomena after nerve injury [ 46 ], and the cytokine GRO/KC shows upregulation in dorsal root ganglion after nerve injury, appearing to have a pro-nociceptive effect by increasing neuronal excitability in small diameter sensory neurons [ 47 ]. Along with MCP-1 and MIP-1α, RANTES also seems to have an important role in the recruitment of macrophages, but having a modulating effect on the secretion of proinflammatory cytokine proteins and regulating the inflammatory microenvironment at the site of injury [ 48 , 49 ].…”

Effects of Olfactory Mucosa Stem/Stromal Cell and Olfactory Ensheating Cells Secretome on Peripheral Nerve Regeneration

“…Simultaneously, some anti-inflammatory cytokines such as IL-10 are also upregulated at this stage, probably contributing to the balance in the immune response and preventing deleterious inflammatory reactions [39]. Fractalkine participates in a signaling pathway in neuron-to-microglia communication and is related to the development of neuropathic pain phenomena after nerve injury [44], and the cytokine GRO/KC shows upregulation in dorsal root ganglion after nerve injury, appearing to have a pro-nociceptive effect by increasing neuronal excitability in small diameter sensory neurons [45]. Along with MCP-1 and MIP-1α, RANTES also seems to have an important role in the recruitment of macrophages, but having a modulating effect on the secretion of proinflammatory cytokine proteins and regulating the inflammatory microenvironment at the site of injury [46,47].…”