Figure 4.

Schematic diagram of augmented Ang II from CD3⁺ T cells and possibly other cells signalling through the AT₂ receptor on peripheral macrophages to generate reactive oxygen species and/or reactive nitrogen species (ROS and/or RNS) that transactivates the TRPA1 receptor on DRG neurons resulting in neuronal hyperexcitability, a hallmark of peripheral neuropathic pain. Augmented Ang II signalling by the AT₂ receptor also induces activation of p38 MAPK and pERK1/2 that is reduced by a single bolus dose of small molecule AT₂ receptor antagonists at the time of peak effect to match the corresponding levels in the sham controls. Augmented Ang II signalling via the AT₂ receptor also reduces levels of pro-NGF and mature NGF in the ipsilateral lumbar DRG with levels of mature NGF restored to match the corresponding levels in the sham controls at the time of peak effect of an AT₂ receptor antagonist. The precise interplay between TRPA1 receptor activation, increased expression levels of pp38 MAPK and pERK1/2, and reduced expression levels of pro-NGF and mature NGF in the ipsilateral lumbar DRG in rodent pain models is currently unclear and remains to be defined. Ang II, angiotensin II; AT₂, angiotensin II type 2; DRG, dorsal root ganglia; MAPK, mitogen-activated protein kinase; NGF, nerve growth factor.