Fractalkine CX3CR1 and neuropathic pain

Fractalkine is a remarkable chemokine constitutively expressed by neurons, and its only receptor, CX3CR1, is expressed by microglia.

73350100-Rostislav-Zatonskiy-Dreamstime-INP-Instituut-voor-Neuropathische-Pijn cisplatinumThe 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.

Inflammation and nerve injury increased spinal cord CX3CR1 and Fractalkine expression. Loss of the Fractalkine/CX3CR1 interaction attenuates hyperalgesia and allodynia in pathological pain models.[1]

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.[2]

Soluble Fractalkine is up-regulated under many inflammatory conditions and neuron injury, even ones associated with hepatocellular carcinoma development.[3] 

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 

Fractalkine and neuropathic painIn 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.[4] Fractalkine might even play a role in human tauopathies.[5]

And this definitely holds true for neuropathic or gliopathic pain.[6]

October 2010, Jan M. Keppel Hesselink, MD, PhD
‘Fractalkine CX3CR1 and neuropathic pain’

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[1] Staniland AA, Clark AK, Wodarski R, Sasso O, Maione F, D'Acquisto F, Malcangio M. | Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. | J Neurochem. | 2010 Aug;114(4):1143-57. Epub 2010 May 28.

[2] Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR. | Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. | Brain Behav Immun. | 2007 Jul;21(5):642-51. Epub 2006 Dec 15.

[3] Turner SL, Mangnall D, Bird NC, Blair-Zajdel ME, Bunning RA. | Effects of pro-inflammatory cytokines on the production of soluble fractalkine and ADAM17 by HepG2 cells. | J Gastrointestin Liver Dis. | 2010 Sep;19(3):265-71.

[4] Ceyhan GO, Deucker S, Demir IE, Erkan M, Schmelz M, Bergmann F, Müller MW, Giese T, Büchler MW, Giese NA, Friess H. | Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis. | Lab Invest. | 2009 Mar;89(3):347-61. Epub 2009 Jan 19.

[5] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. | Regulation of tau pathology by the microglial fractalkine receptor. | Neuron. | 2010 Oct 6;68(1):19-31.

[6] Gao YJ, Ji RR. | Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. | Pharmacol Ther. | 2010 Apr;126(1):56-68. Epub 2010 Feb 1.

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