Metformin: A Prospective Alternative for the Treatment of Chronic Pain

Abstract

Metformin (biguanide) is a drug widely used for the treatment of type 2 diabetes. This drug has been used for 60 years as a highly effective antihyperglycemic agent. The search for the mechanism of action of metformin has produced an enormous amount of research to explain its effects on gluconeogenesis, protein metabolism, fatty acid oxidation, oxidative stress, glucose uptake, autophagy and pain, among others. It was only up the end of the 1990s and beginning of this century that some of its mechanisms were revealed. Metformin induces its beneficial effects in diabetes through the activation of a master switch kinase named AMP-activated protein kinase (AMPK). Two upstream kinases account for the physiological activation of AMPK: liver kinase B1 and calcium/calmodulin-dependent protein kinase kinase 2. Once activated, AMPK inhibits the mechanistic target of rapamycin complex 1 (mTORC1), which in turn avoids the phosphorylation of p70 ribosomal protein S6 kinase 1 and phosphatidylinositol 3-kinase/protein kinase B signaling pathways and reduces cap-dependent translation initiation. Since metformin is a disease-modifying drug in type 2 diabetes, which reduces the mTORC1 signaling to induce its effects on neuronal plasticity, it was proposed that these mechanisms could also explain the antinociceptive effect of this drug in several models of chronic pain. These studies have highlighted the efficacy of this drug in chronic pain, such as that from neuropathy, insulin resistance, diabetic neuropathy, and fibromyalgia-type pain. Mounting evidence indicates that chronic pain may induce anxiety, depression and cognitive impairment in rodents and humans. Interestingly, metformin is able to reverse some of these consequences of pathological pain in rodents. The purpose of this review was to analyze the current evidence about the effects of metformin in chronic pain and three of its comorbidities (anxiety, depression and cognitive impairment).

Keywords: AMPK activation; anxiety; chronic pain; depression; diabetes; diabetic neuropathy; metformin; neuropathic pain.

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.