Fractalkine CX3CR1 and neuropathic pain
Fractalkine is a remarkable chemokine constitutively expressed by neurons, and its only receptor, CX3CR1, is expressed by microglia.
The chemokine Fractalkine therefore is a one of the new kids on the block in neuropathic pain and is seen as a key mediator of spinal neuronal-microglial communication. Fractalkine induces migration of inflammatory cells into inflamed tissues, thereby aggravating inflammatory tissue damage and fibrosis.
Fractalkine is enzymatically cleaved from neuronal membranes. It has its own receptor, the CX3CR1 receptor, and this receptor is expressed by microglia. The activated receptor induces phosphorylation of p38 MAPK.
Intrathecal infusion of Fractalkine produces a marked p38 activation and is the cause of mechanical allodynia. Fractalkine cleavage and release after nerve injury is seen as playing an important role in neural-glial interaction. And might be critical for the development of neuropathic pain.
Soluble Fractalkine is up-regulated under many inflammatory conditions and neuron injury, even ones associated with hepatocellular carcinoma development.
Fractalkine increases neuropathic pain through glial activation, which can be diminished by blocking of its receptor, CX3CR1, through neutralizing antibodies.
Fractalkine and chronic pancreatic pain
In a chronic pancreatitis (CP) model, characterized by tissue infiltration of inflammatory cells, fibrosis, pancreatic neuritis and severe pain, the roles of Fractalkine and CX3CR1 were investigated in CP (n=61) and normal pancreas (NP, n=21).
Their expression correlated with the severity of pancreatic neuritis, fibrosis, intrapancreatic nerve fiber density and hypertrophy, pain, CP duration and with the amount of inflammatory cell infiltrate immuno-positive for CD45 and CD68.
The researchers concluded:
Long-term suffering from CP was noticeably related to increased neural immunoreactivity of Fractalkine. Furthermore, Fractalkine and CX3CR1 mRNA overexpressions were associated with enhanced lymphocyte and macrophage infiltration. Advanced fibrosis was associated with increased Fractalkine expression, whereas in vitro Fractalkine had no significant impact on collagen-1 and alpha-SMA expressions in hPSCs.
Therefore, pancreatic Fractalkine expression appears to be linked to visceral pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However, pancreatic fibrogenesis is probably indirectly influenced by Fractalkine.
Taken together, these novel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduce inflammation and modulate pain in CP. Fractalkine might even play a role in human tauopathies.
And this definitely holds true for neuropathic or gliopathic pain.
October 2010, Jan M. Keppel Hesselink, MD, PhD
‘Fractalkine CX3CR1 and neuropathic pain’
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