Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury

Abstract

Rapamycin is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, plays an important role in multiple cellular functions. Our previous study showed rapamycin treatment in acute phase reduced the neural tissue damage and locomotor impairment after spinal cord injury (SCI). However, there has been no study to investigate the therapeutic effect of rapamycin on neuropathic pain after SCI. In this study, we examined whether rapamycin reduces neuropathic pain following SCI in mice. We used a mouse model of thoracic spinal cord contusion injury, and divided the mice into the rapamycin-treated and the vehicletreated groups. The rapamycin-treated mice were intraperitoneally injected with rapamycin (1 mg/kg) 4 h after SCI. The rapamycin treatment suppressed phosphorylated-p70S6K in the injured spinal cord that indicated inhibition of mTOR. The rapamycin treatment significantly improved not only locomotor function, but also mechanical and thermal hypersensitivity in the hindpaws after SCI. In an immunohistochemical analysis, Iba-1-stained microglia in the lumbar spinal cord was significantly decreased in the rapamycin-treated mice. In addition, the activity of p38 MAPK in the lumbar spinal cord was significantly attenuated by rapamycin treatment. Furthermore, phosphorylated-p38 MAPK-positive microglia was relatively decreased in the rapamycin-treated mice. These results indicated rapamycin administration in acute phase to reduce secondary neural tissue damage can contribute to the suppression of the microglial activation in the lumbar spinal cord and attenuate the development of neuropathic pain after SCI. The present study first demonstrated that rapamycin has significant therapeutic potential to reduce the development of neuropathic pain following SCI.

MicroRNA-183 Suppresses Neuropathic Pain and Expression of AMPA Receptors by Targeting mTOR/VEGF Signaling Pathway

“…Tateda S et al demonstrated that rapamycin, as an inhibitor of mTOR, suppressed the development of neuropathic pain when the spinal cord was injured [36]. These studies consisted with our observation that the inhibition of mTOR can significantly attenuate symptoms of neuropathic pain.…”

Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior

“…In microglia (CD11/OX42+), mTOR signaling is increased in response to oxidative stress, hypoxia, and cytokines including TNFα [49] and IL-1β, and modulates the production of nitric oxide [117]. mTOR signaling could also contribute to activation of microglia, as blockade of mTOR with rapamycin decreases numbers of activated microglia [118, 119]. Therefore, increases in p-mTOR-positive astrocytes in the voluntary exercise condition could contribute to the beneficial effects of exercise on neuronal health and plasticity, whereas an increase of p-mTOR-positive microglia following forced wheel running could be a consequence of, or contributor to, cellular stress and inflammation.…”

Inhibition of Mammalian Target of Rapamycin (mTOR) Signaling in the Insular Cortex Alleviates Neuropathic Pain after Peripheral Nerve Injury

“…Rapamycin has been used as an anticancer and immunosuppressive agent in clinical treatment (Populo et al, 2012; Tateda et al, 2017). Because the side effects from rapamycin are relatively low compared to with other drugs, it has also been widely used in chronic pain treatments (Lee et al, 2006; Alamo et al, 2009).…”