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Pharmacol Res. 2019 Jan;139:1-16. doi: 10.1016/j.phrs.2018.10.027. Epub 2018 Nov 1.

The antidiabetic drug metformin prevents and reverses neuropathic pain and spinal cord microglial activation in male but not female mice.

Author information

1
School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, United States.
2
School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, United States. Electronic address: Michael.burton@utdallas.edu.
3
School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, United States. Electronic address: Theodore.price@utdallas.edu.

Abstract

Metformin is a widely prescribed drug used in the treatment of type II diabetes. 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. Activation of 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 have previously shown that metformin leads to an enduring resolution of neuropathic pain in the spared nerve injury (SNI) model in male mice and rats. The precise mechanism underlying this long-lasting effect is not known. 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. We find that metformin is effective at inhibiting development of neuropathic pain when treatment is given around the time of injury and that metformin is likewise effective at reversing neuropathic mechanical hypersensitivity when treatment is initiation weeks after injury. This effect is linked to decreased Iba-1 staining in the dorsal horn, a marker of microglial activation. Importantly, these positive behavioral and microglia effects of metformin were only observed in male mice. We conclude that the neuropathic pain modifying effects of metformin are sex-specific supporting a differential role for microglial activation in male and female mice.

KEYWORDS:

AMPK; Metformin; Microglia; Neuropathic pain; Pain

PMID:
30391353
PMCID:
PMC6447087
DOI:
10.1016/j.phrs.2018.10.027
[Indexed for MEDLINE]
Free PMC Article

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