Pain-Relieving Effects of mTOR Inhibitor in the Anterior Cingulate Cortex of Neuropathic Rats

Abstract

The anterior cingulate cortex (ACC) is a well-known brain area that is associated with pain perception. Previous studies reported that the ACC has a specific role in the emotional processing of pain. Chronic pain is characterized by long-term potentiation that is induced in pain pathways and contributes to hyperalgesia caused by peripheral nerve injury. The mammalian target of rapamycin (mTOR) signaling, which is involved in synaptic protein synthesis, could be a key factor controlling long-term potentiation in neuropathic pain conditions. Until now, there have been no reports that studied the role of mTOR signaling in the ACC involved in neuropathic pain. Therefore, this study was conducted to determine the relationship of mTOR signaling in the ACC and neuropathic pain. Male Sprague-Dawley rats were subjected to cannula implantation and nerve injury under pentobarbital anesthesia. Microinjection with rapamycin into the ACC was conducted under isoflurane anesthesia on postoperative day (POD) 7. A behavioral test was performed to evaluate mechanical allodynia, and optical imaging was conducted to observe the neuronal responses of the ACC to peripheral stimulation. Inhibition of mTOR by rapamycin reduced mechanical allodynia, down-regulated mTOR signaling in the ACC, and diminished the expressions of synaptic proteins which are involved in excitatory signaling, thereby reducing neuropathic pain-induced synaptic plasticity. These results suggest that inhibiting mTOR activity by rapamycin in the ACC could serve as a new strategy for treating or managing neuropathic pain before it develops into chronic pain.

Effects of Early Exposure of Isoflurane on Chronic Pain via the Mammalian Target of Rapamycin Signal Pathway

“…The mTOR protein is an obligatory component of two complexes (mTORC1 and mTORC2) which are at the center of a signaling system that regulates cellular activities including proliferation, differentiation, apoptosis, metabolism, transmitter release, synaptic formation, and other biological processes [31]. In the intact rat model, mTOR and several downstream molecules, such as eukaryotic inhibition factor 4E-binding protein (4E-BP) and p70 ribosomal S6 protein kinase (p70S6K), were expressed in IC, ACC, SDH, and dorsal root ganglion (DRG); however, the level of p -mTOR was a very low level [22,24,44]. It has been reported that in a variety of pathological conditions, such as injury or nociceptive stimulation that stimulate pain, that the activity of mTOR pathway molecules, as evidenced by phosphorylation of mTOR, is dramatically increased [22,24,45], a finding that our results have replicated.…”

“…In the intact rat model, mTOR and several downstream molecules, such as eukaryotic inhibition factor 4E-binding protein (4E-BP) and p70 ribosomal S6 protein kinase (p70S6K), were expressed in IC, ACC, SDH, and dorsal root ganglion (DRG); however, the level of p -mTOR was a very low level [22,24,44]. It has been reported that in a variety of pathological conditions, such as injury or nociceptive stimulation that stimulate pain, that the activity of mTOR pathway molecules, as evidenced by phosphorylation of mTOR, is dramatically increased [22,24,45], a finding that our results have replicated. Early isoflurane exposure increased the number of immunolabeled neurons for pS6, a reliable downstream reporter for mTOR pathway activity, in IC, ACC, and superficial DSH (Figure 2, Figure 3 and Figure 4).…”

“…We focused on two cortical regions that are involved in pain transduction and modulation—the insular cortex (IC) and anterior cingulate cortex (ACC)—and on the spinal cord dorsal horn (SDH). IC and ACC have been implicated as important centers for pain information memory [22,23,24,25] and SDH is a critical area for regulation and transmission of pain signal [26]. In our previous work, we have found that early developmental isoflurane exposure aberrantly increases activity in the mammalian target of rapamycin (mTOR) pathway [27,28,29], which is a complex system that interpolates between extracellular cues and intracellular signaling systems that regulates a variety of biological processes [30,31], including central nervous system (CNS) development [32].…”

Manganese-enhanced MRI depicts a reduction in brain response to nociception by mTOR inhibition in chronic pain rats

“…Modulation of chronic pain through mTOR inhibition is a newly studied application target for chronic pain control [16,36]. Previous studies have observed changes in chronic pain through the inhibition of mTOR signaling in the spinal cord [37][38][39][40], and recent studies have demonstrated effective modulation of chronic pain by direct mTOR signaling control in the brain [16,41], The activation of mTOR regulates protein synthesis by phosphorylating downstream effectors, which in uence a wide range of physiological and pathological states including neuropathic, in ammatory, and cancer-related pain [16][17][18], The Torin1 and XL388 used in this study were ATP-competitive inhibitors that suppress the phosphorylation of downstream effectors to regulate mRNA translation and protein synthesis [42].…”

Manganese-enhanced MRI depicts a reduction in brain response to nociception upon mTOR inhibition in chronic pain rats

“…Modulation of chronic pain through mTOR inhibition is a newly studied target for chronic pain control [16,37]. Previous studies have observed changes in chronic pain through the inhibition of mTOR signaling in the spinal cord [38][39][40][41], and recent studies have demonstrated effective modulation of chronic pain by direct mTOR signaling control in the brain [16,32,42], The activation of mTOR regulates protein synthesis by phosphorylating downstream effectors, which in uence a wide range of physiological and pathological states, including neuropathic, in ammatory, and cancer-related pain [16][17][18]. The mTOR inhibitors Torin1 and XL388 used in this study are ATP-competitive inhibitors that suppress the phosphorylation of downstream effectors to regulate mRNA translation and protein synthesis [43].…”