Table 1.

Pathophysiologic effects of proinflammatory cytokines

Cellular activation – neurons, glia, Schwann cells, mast cells, endothelial cells, and macrophages Increased sensitivity of cells leading to structural and functional changes that can produce pain Spontaneous electrophysiologic activity Aberrant activity in polymodal nociceptive fibers Upregulation of voltage-gated sodium channels Production of new pain-related sodium channels Degradation of matrix metalloproteinases Disruption of vascular and perineurial/meningeal barriers upsetting local chemical environment and causing edema Macrophage chemoattraction Powerful signals distributed locally and systemically that attract macrophages and other immuno-competent cells. Increase activity of vascular adhesion molecules Local upregulation promotes attachment and invasion of immune cells, particularly macrophages to the site of injury Proinflammatory cytokine receptor upregulation Upregulation of cytokine receptors increases density of receptors at site of injury and increases the local effects of the cytokines Proinflammatory cytokine upregulation Positive feedback loop locally produces enhanced effect of inflammatory cytokines. Negative feedback loop can cause upregulation of anti-inflammatory cytokines Upregulation of spinal nociceptive mediators Chemical and functional changes in dorsal horn activity and other central neuronal changes