The mTOR Signaling Pathway Regulates Pain-Related Synaptic Plasticity in Rat Entorhinal-Hippocampal Pathways

Abstract

BackgroundOur previous work demonstrated that persistent peripheral nociception (PPN) leads to synaptic plasticity and functional changes in the rat hippocampus. The protein kinase mTOR is a critical regulator of protein synthesis-dependent synaptic plasticity in the hippocampus as well as synaptic plasticity associated with central and peripheral pain sensitization. We examined the role of mTOR signaling in pain-associated entorhinal cortex (EC) - hippocampal synaptic plasticity to reveal possible cellular mechanisms underlying the effects of chronic pain on cognition and emotion.ResultsSubcutaneous injection of bee venom (BV) into one hind paw to induce PPN resulted in sustained (> 8 h) mTOR phospho-activation and enhanced phosphorylation of the mTOR target p70 S6 kinase (S6K) in the hippocampus. The magnitude and duration of long-term potentiation (LTP) in both EC - dentate gyrus (DG) and EC - CA1 synaptic pathways were elevated in BV-treated rats as measured by microelectrode array recording. Moreover, the number of potentiated synapses in the hippocampus was markedly upregulated by BV-induced PPN. Both elevated mTOR-S6K signaling and enhanced LTP induced by BV injection were reversed by systemic injection of the mTOR inhibitor rapamycin (RAPA). Rats injected with BV exhibited markedly reduced ambulation and exploratory activity in the open field (signs of depression and anxiety) compared to controls, and these effects were also reversed by RAPA.ConclusionWe suggest that PPN-induced enhancement of synaptic plasticity in EC - hippocampal pathways and the behavioral effects of PPN are dependent on mTOR-S6K signaling.

Electroacupuncture Reduces the Effects of Acute Noxious Stimulation on the Electrical Activity of Pain-Related Neurons in the Hippocampus of Control and Neuropathic Pain Rats

“…The dorsal hippocampal dopamine receptors exert an analgesic effect during the orofacial pain test [28]; microinjections of nonsteroidal anti-inflammatory drugs [29] or 2-AG [30] into the hippocampus induce antinociception. A recent study indicates that persistent peripheral nociception induced by subcutaneous injection of bee venom upregulated mTOR target p70 S6 kinase signaling and facilitated long-term potentiation which could be reversed by mTOR inhibitor in the hippocampus [31]. …”

mTOR in Brain Physiology and Pathologies

“…mTORC1 is activated in hippocampus following persistent peripheral nociception and participates in LTP in the dentate gyrus and at CA1 synapses, which is blocked by rapamycin. Thus the mTORC1 pathway may be an important target for controlling chronic pain and its effects on cognition and emotion (172,208).…”

Autophagy in synaptic development, function, and pathology

“…Notably, mTOR regulates local RNA translation at the synapse and thus appears to be important for the synthesis of synaptic proteins [39] . Emerging lines of evidence highlight the crucial role of the mTOR signal in regulating synaptic transmission [40,41] and synaptic plasticity [42] . Inhibition of the mTOR signaling pathway by rapamycin, which upregulates autophagic activity in mammalian cells, reduces the numbers of synaptic vesicle and depresses the evoked dopamine (DA) secretion from dopaminergic neurons [40] (Fig.…”