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

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.

Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury

“…Female rats have been reported to both increase (29) and decrease (30) the prevalence of developing mechanical and thermal allodynia after SCI, while no sexdependent effects have been found in mice (31,32). Importantly, several studies investigating analgesic strategies to reduce pain caused by peripheral nerve injury have converging evidence that many pain-relieving agents exert sexually dichotomous effects (33)(34)(35)(36)(37)(38). A similar sex-dependent effect was found using pioglitazone to treat SCI-induced pain in mice which found a female-specific analgesic influence (31).…”

Metformin and cognition from the perspectives of sex, age, and disease

“…Interestingly, sex of the species and location of microglia determine the impact of metformin on microglia, as shown by selective microglial activation and reversal of neuropathic pain in male mice. (Inyang et al 2019).…”

Macrophage Toll-like Receptor 9 Contributes to Chemotherapy-Induced Neuropathic Pain in Male Mice

“…Notably, microglia drive neuropathic pain and inflammatory pain in male animals (Rosen et al, 2017). Several microglial signaling molecules, including Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (MAPK), ATP receptor P2X4, and BDNF, exhibit sexually dimorphic functions in inflammatory and neuropathic pain (Sorge et al, 2011(Sorge et al, , 2015Taves et al, 2016;Luo et al, 2018;Mapplebeck et al, 2018;Inyang et al, 2019). Upstream activators of microglia, such as caspase-6, also display male-specific activity in the contexts of inflammatory and neuropathic pain (Berta et al, 2016;Chen et al, 2018).…”