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. 2020 Sep 23;11:558474. doi: 10.3389/fphar.2020.558474

Figure 1.

Figure 1

Current mechanisms proposed for metformin in pathological pain. The mTOR/P70S6K/4E-BP1/rS6P pathway activates formation of the eIF4F complex and promotes aberrant translation in nociceptors during pathological pain. Also, activation of mitogen-activated protein kinase (MAPK), inflammation and protein kinase A (PKA) pathways lead to pain plasticity. Metformin acts as a disease-modifying drug by indirectly activating AMPK. Once activated, phosphorylated AMPK inhibits the mTORC1 pathways reversing pain plasticity and pathological pain. Metformin also inhibits glucagon actions to induce its antihyperglycemic effect in diabetic conditions. However, the role of this pathway on pain has not been explored. LKB1, Liver kinase B1; CaMKK2, Calcium/calmodulin-dependent protein kinase kinase 2; IPMK, Inositol polyphosphate multikinase; AMPK, AMP-activated protein kinase; Rheb, GTP-bound Rheb GTPase; mTORC1, Mechanistic target of rapamycin complex 1; P70S6K, 70 kDa ribosomal protein S6 kinase; 4E-BP1, Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1; rS6P, S6 ribosomal protein; eIF4F: Eukaryotic translation initiation factor 4F; nNOS, Neuronal nitric oxide synthase; NF-kβ: Nuclear factor kappa β; TNFα, Tumor necrosis factor α; IFNγ, interferon-γ.