Work

261. In Vivo Over-Expression of Fractalkine, a Putative Neuron-to-Glia Signal, To Characterize Underlying Mechanisms of Neuropathic Pain

Year: 2006

Type: article

Abstract: We have previously shown that fractalkine (FKN), the newest member of the chemokine family, plays an integral role in the initiation and maintenance of exaggerated pain states. Fractalkine is expressed on the external surface of sensory nerves and some dorsal spinal cord neurons. The receptor for FKN is found predominately on spinal cord microglia. Strong neuronal excitation induces the cleavage of the FKN chemokine domain forming a soluble signal that can act on nearby glia. Spinal cord microglia are important in diverse forms of enhanced pain states via the release of the pro-inflammatory cytokines, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF). We have shown that the pain-enhancing effects of spinally administered (via intrathecal injection) FKN are mediated, at least in part, via release of the glial proinflammatory cytokine, IL-1.Thus FKN may be a neuron-to-glia signal that triggers glial activation and consequent pain facilitation. To further elucidate the underlying mechanisms of FKN's role in neuropathic pain, we have engineered plasmid expression vectors encoding soluble forms of the active chemokine domain, CX3CL1. Concurrent studies are designed to determine whether two sequential intrathecal injections, each 100 μg in 20 μL of C X3CL1 plasmid leads to chronic neuropathic pain as measured by hypersensitivity to light mechanical stimuli presented to the hind paws of rats. Exaggerated pain will be reassessed every four days to determine the duration of FKN- induced hypersensitivity. Further we will determine levels of FKN expression in cerebrospinal fluid and spinal cord microglial activation. Additional studies will examine the pro-inflammatory cytokine profile (IL-1, IL-6, and TNF) in cerebrospinal fluid after chronic FKN over-expression in behaviorally verified rats. This system should allow for the examination of newly developed FKN antagonists to treat neuropathic pain.

Source: Molecular Therapy

DOI: 10.1016/j.ymthe.2006.08.288