Contributions of mTOR Activation-Mediated Upregulation of Synapsin II and Neurite Outgrowth to Hyperalgesia in STZ-Induced Diabetic Rats

Abstract

Painful diabetic neuropathy (PDN) is among the common complications in diabetes mellitus (DM), with its underlying mechanisms largely unknown. Synapsin II is primarily expressed in the spinal dorsal horn, and its upregulation mediates a superfluous release of glutamate and a deficiency of GABAergic interneuron synaptic transmission, which is directly implicated in the facilitation of pain signals in the hyperalgesic nociceptive response. Recently, synapsin II has been revealed to be associated with the modulation of neurite outgrowth, whereas the process of this neuronal structural neuroplasticity following neuronal hyperexcitability still remains unclear. In this study, we found that under conditions of elevated glucose, TNF-α induced the activation of mTOR, mediating the upregulation of synapsin II and neurite outgrowth in dorsal horn neurons. In vivo, we demonstrated that mTOR and synapsin II were upregulated and coexpressed in the spinal dorsal horn neurons in rats with streptozotocin (STZ)-induced diabetes. Furthermore, the intrathecal administration of the mTOR inhibitor rapamycin or synapsin II shRNA significantly diminished the expression of synapsin II, effectively mitigating hyperalgesia in PDN rats. We are the first to discover that in STZ-induced diabetic rats the activation of mTOR mediates the upregulation of synapsin II and neurite outgrowth, both contributing to hyperalgesia. These findings may benefit the clinical therapy of PDN by provision of a novel target.

Abnormal Insulin-like Growth Factor 1 Signaling Regulates Neuropathic Pain by Mediating the Mechanistic Target of Rapamycin-Related Autophagy and Neuroinflammation in Mice

“…31 Similarly, our recent finding demonstrated that mTOR signaling is essential for the development of painful diabetic neuropathy. 16 Here, we also observed the activation of mTOR signaling in the spinal cord, as indicated by the elevation in the p-mTOR and p-S6K (a downstream effector of mTOR). However, these alterations could be reversed by i.t.…”

“…18,19 Our recent study has found that mTOR plays a vital role in diabetes-related neuropathic pain. 16 Thus, we detected the phosphorylation level of p-mTOR at ser2448 and its downstream S6K. 20 Furthermore, we found that the protein levels of p-mTOR and p-S6K were We also analyzed the production of pro-inflammatory cytokines.…”

“…Recent in vitro evidence reveals that IGF1 signaling suppresses autophagy in osteocyte-like MLO-Y4 cells and dopaminergic neurons by activating the mechanistic target of the rapamycin (mTOR)-related signaling cascade. Our previous works have also reported the contribution of aberrant mTOR activation to mechanical hyperalgesia in painful diabetic neuropathy …”

“…Our previous works have also reported the contribution of aberrant mTOR activation to mechanical hyperalgesia in painful diabetic neuropathy. 16 T h i s c o n t e n t i s Therefore, we hypothesize that IGF1 signaling might be involved in the pathogenesis of neuropathic pain by regulating mTOR-mediated autophagy. To test this hypothesis, we established the neuropathic pain model via CCI operation, examined the expression of IGF1 and IGF1R in the spinal cord, and investigated whether inhibiting IGF1 signaling affects pain-like behaviors after CCI.…”

Sigma‐1 receptor antagonist (BD‐1063) potentiates the antinociceptive effect of quercetin in neuropathic pain induced by chronic constriction injury

“…The phosphorylation of mTOR and p70S6K in the spinal dorsal horn is increased in neuropathic pain models and administration of the mTOR inhibitor rapamycin effectively mitigates hyperalgesia in these models, in that context, QUER could alleviate neuropathic pain by inhibiting mTOR/p70S6K pathway‐mediated changes in synaptic morphology and synaptic function, as demonstrated in an experimental model of diabetic neuropathy (Wang et al, 2020). Another mechanism by which QUER generates a decrease in sensitivity in this work could be explained by its effect on the regulation of the P2X4 receptor (Yang et al, 2019), since the P2X4 receptor contributes to inflammatory pain and neuropathic pain (Cho et al, 2018; He et al, 2019; Wang et al, 2020) and studies have shown that peripheral nerve injury can increase the expression and activation of P2X4 in the DRG as a key factor in the initiation and sustained development of neuropathic pain (Yang et al, 2019; Ying et al, 2017). In summary, these mechanisms favor the decrease in hypersensitivity shown in CCI rats when QUER is administered.…”