The Role of AMPK Activation in the Attenuation of Chronic Pain




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Chronic pain is a serious medical condition that impacts over 100 million Americans each year. Metformin is a widely prescribed drug used in the treatment of type II diabetes that has been repurposed as an analgesic. While the drug has many mechanisms of action, most of these converge on AMP activated protein kinase (AMPK), which metformin activates. AMPK is a multifunctional kinase that is a negative regulator of mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling. Activating AMPK decreases the excitability of dorsal root ganglion neurons and AMPK activators are effective in reducing chronic pain in inflammatory, post-surgical and neuropathic rodent models. We explored the behavioral effects of metformin in the SNI model in males and females. We are also aware of potential sex differences in microglia, immune cells of the CNS that play a key role in pain. We conducted experiments to investigate the effects of metformin on SNI-induced microglial activation, a process implicated in the maintenance of neuropathic pain that has recently been shown to be sexually dimorphic. Metformin cause a decrease in mechanical hypersensitivity, cold allodynia and microglial activation in male mice but not in females. We then explored the effects of positive allosteric modulators of AMPK and indirect upstream activators of AMPK in male and female mice to treat incision-induced and paclitaxel-induced mechanical hypersensitivity. We used metformin as well as other structurally distinct AMPK activators, narciclasine (NCLS), ZLN 024 and MK 8722, to treat incision-induced and mechanical hypersensitivity and hyperalgesic priming in male and female mice. We found that metformin was the only AMPK activator to have sex specific effects. Indirect AMPK activators metformin and NCLS were able to reduce mechanical hypersensitivity and block hyperalgesic priming, direct AMPK activators, ZLN 024 and MK 8722 only blocked priming. Direct and indirect AMPK activators stimulated AMPK in DRG cultures to a similar degree. These AMPK activators were also tested for their ability to prevent and reverse paclitaxel-induced mechanical hypersensitivity. Drugs were given concurrently with paclitaxel then after the completion of paclitaxel treatment to test whether they prevent and reverse established mechanical hypersensitivity respectively. Unlike metformin, narciclasine also reversed mechanical hypersensitivity in established chemotherapy-induced peripheral neuropathy (CIPN). Both metformin, narciclasine and MK8722 prevented the development of hyperalgesic priming induced by paclitaxel treatment. MK8722 had no effect on mechanical hypersensitivity caused by paclitaxel in either the prevention or reversal treatment paradigms. Incision and CIPN decreased phosphorylated AMPK (p-AMPK) in DRG. Because AMPK phosphorylation is required for kinase activity, we concluded that indirect AMPK activators are more effective for treating pain hypersensitivity after incision or paclitaxel treatment because they can drive increased p-AMPK through upstream kinases like liver kinase B1 (LKB1). Conversely, direct allosteric modulators of AMPK have decreased efficacy due to this injury-induced decrease in p-AMPK. From this, we concluded that indirect AMPK activators are more effective than positive allosteric modulators in producing disease modifying effects in chronic pain models. Moreover, the lack of sex-differences seen with narciclasine make it a particularly attractive candidate for subsequent preclinical pain research.



Protein kinases, Chronic pain--Treatment, Medical care--Utilization--Sex differences


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