Fig. (2).

Polarization of microglia. Microglial cell polarization is categorized into the classical activation state (M1), which exhibits harmful properties, and an alternative activation state (M2), which demonstrates protective and reparative functions. Depending on the environmental influences, the microglia shift their functions to maintain tissue homeostasis. Stimulation with harmful factors (e.g. LPS or IFNγ) moves the cells toward the M1 phenotype and induces the expression of proinflammatory mediators with pro-nociceptive properties (IL-1β, IL-6, IL-12, IL-15, IL-18, CCL2, CCL3, CCL4, CCL5, CCL7, IFNγ, TNFα, iNOS, COX-2, MMP-2, MMP-9, NO, ROS). However, stimulation with anti-inflammatory compounds, such as IL-4 and IL-13, promotes the M2 state, deactivates the pro-inflammatory cell phenotype, restores homeostasis and induces the increased expression of mediators with analgesic features (such as IL-1α, IL-1ra, IL-3, IL-10, IL-18BP, TIMP1, Arg1, NGF, TGFβ. Microglial cells polarization is differentially activated by intracellular signaling cascades (MAPKs, NF-κB, JAK/STAT, PI3K/Akt) that are essential for neuropathic pain development and maintenance.