Abstract
There is abounding evidence that neuroinflammation plays a major role in the pathogenesis of neurodegeneration and neuropathic pain. Chemokine-induced recruitment of peripheral immune cells is a central feature in inflammatory neurodegenerative disorders. Immune cells, glial cells and neurons constitute an integral network that coordinates the immune response by releasing inflammatory mediators that in turn modulate inflammation, neurodegeneration and the signal transduction of pain, via interaction with neurotransmitters and their receptors. The chemokine monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand (MCP-1/CCL2) and its receptor C-C chemokine receptor (CCR2) play a major role in mediating neuroinflammation and targeting CCL2/CCR2 represents a promising strategy to limit neuroinflammation-induced neuropathy. In addition, the CCL2/CCR2 axis is also involved in mediating the pain response. Key cellular signaling events such as phosphorylation and subsequent activation of mitogen activated protein kinase (MAPK) p38 and its substrate MAPK-activated protein MAPKAP Kinase (MK) MK-2, regulate neuroinflammation, neuronal survival and synaptic activity. Further, MAPKs such as extracellular signal-regulated kinases (ERK), c-jun N-terminal kinase (JNK) and p38 play vital roles in mediating the pain signaling cascade and contribute to the maintenance of peripheral and central neuronal sensitization associated with chronic pain. This review outlines the rationale for developing therapeutic strategies against CCL2/CCR2 and MAPK signaling networks, identifying them as novel therapeutic targets for limiting neuroinflammation and neuropathic pain.