Figure 9. Overview of DRG neuron signaling pathways involved in inflammatory pain hypersensitivity.

Injection of carrageenan stimulates the synthesis and/or secretion of inflammatory products (1) including PGE2, which in turn activate multiple membrane receptors/signaling pathways (2) and production of reactive oxygen species (ROS) (3). ROS may reduce the level of membrane cholesterol (4) and/or directly oxidate Nav1.9 channels, among others (5). This causes neuronal hypersensitization (6) that transforms nociceptor phenotype to pathophysiologic states of persistent nociceptor activation, lowered firing thresholds, and/or exaggerated pain responses.