Figure 11.

COX-2 feedback loop transcriptionally regulated by ATF3. TLR4 is activated by cellular debris from neuronal injury as well as certain cytokines, which then activates parts of the MAPK signaling cascade as well as NF-κB. Production of PGE₂ provides a positive feedback loop to support continued production of prostaglandin, which further support increased immune cell infiltration and activation. PKA, which is activated through PGE₂ binding to its EP4 receptor, can phosphorylate TRPV1 inducing translocation of the receptor to the cell membrane; thereby, increasing neuronal hypersensitivity. Model influenced by our research and multiple citations [33,62,65,66]. Figure made with BioRender.