Figure 2:

The schematic diagram depicts the signaling cascade believed to result in periprosthetic pain following a lumbar total disc replacement. Wear debris activates macrophages and fibroblasts through toll-like receptor 2 (TLR2) and leads to the secretion of several cytokines including interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and activation of the transcription factor nuclear factor-kappa B (NF-κB). Those factors propagate an inflammatory response which could result in pain. Activated fibroblasts and nucleus pulposus (NP) cells may also secrete vascular endothelial growth factor (VEGF) resulting in neovascularization of the disc. The endothelial cells of the new vessels secrete neurotropic factors nerve growth factor (NGF) and brain derived neurotropic factor (BDNF) resulting in neural invasion of the disc alongside the new vessels. The new nerves are unmyelinated and can convey nociceptive signals via substance P and calcitonin gene related peptide (CGRP). Transmission of those signals to the dorsal root ganglion (DRG) can result in pain. The steps highlighted in green represent potential therapeutic targets. Inhibition of inflammatory cytokines IL-1β, TNF-α, and transcription factor NF-κB have been proposed to have therapeutic effect. Additionally, inhibition of TLR2 though receptor antagonists, and VEGF antagonists may also have a role in pain reduction.