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).
Highlights
Acute pain is considered an alarm system for protecting body integrity, while chronic pain may serve an adaptative role (Crook et al, 2014; Lister et al, 2020)
The group of Zhou et al reported for the first time a mechanism to explain the effects of metformin in diabetes. They discovered that metformin was able to induce its anti-diabetic effects by activation of AMPactivated protein kinase (AMPK) in hepatocytes. This activation diminished the expression of lipogenic genes, promoted glucose uptake and suppressed SREBP-1 (Zhou et al, 2001)
Authors of this study reported that metformin was able to activate AMPK and inhibited the mechanistic target of rapamycin complex 1 (mTORC1) pathway in mouse trigeminal (TG) neurons
Summary
Acute pain is considered an alarm system for protecting body integrity, while chronic pain may serve an adaptative role (Crook et al, 2014; Lister et al, 2020). Chronic pain may induce anxiety and depression in rodents and humans (Wang et al, 2019; Zhou et al, 2019). The pharmacotherapy for chronic pain includes tricyclic antidepressants (amitriptyline and nortriptyline), anticonvulsants (gabapentin and pregabalin) and opioids (tramadol and morphine). This pharmacotherapy has limited efficacy and several side effects. Many pre-clinical studies have demonstrated the antinociceptive effects of metformin in rodents Since this drug is a disease-modifying drug in type 2 diabetes, it is likely that it may share these properties to reduce pain and its comorbidities. We assess the current state of evidence regarding the effects of metformin in chronic pathological pain and two of its comorbidities (anxiety/depression and cognitive impairment). Data strongly suggest that metformin could open a new avenue for the treatment of pathological pain and some of its associated comorbidities
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