Abstract
Injury of peripheral nerves can trigger neuropathic pain, producing allodynia and hyperalgesia via peripheral and central sensitization. Recent studies have focused on the role of the insular cortex (IC) in neuropathic pain. Because the IC is thought to store pain-related memories, translational regulation in this structure may reveal novel targets for controlling chronic pain. Signaling via mammalian target of rapamycin (mTOR), which is known to control mRNA translation and influence synaptic plasticity, has been studied at the spinal level in neuropathic pain, but its role in the IC under these conditions remains elusive. Therefore, this study was conducted to determine the role of mTOR signaling in neuropathic pain and to assess the potential therapeutic effects of rapamycin, an inhibitor of mTORC1, in the IC of rats with neuropathic pain. Mechanical allodynia was assessed in adult male Sprague-Dawley rats after neuropathic surgery and following microinjections of rapamycin into the IC on postoperative days (PODs) 3 and 7. Optical recording was conducted to observe the neural responses of the IC to peripheral stimulation. Rapamycin reduced mechanical allodynia and downregulated the expression of postsynaptic density protein 95 (PSD95), decreased neural excitability in the IC, thereby inhibiting neuropathic pain-induced synaptic plasticity. These findings suggest that mTOR signaling in the IC may be a critical molecular mechanism modulating neuropathic pain.
Highlights
Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (Merskey and Bogduk, 1994)
Nerve Injury Leads to the Development of Mechanical Allodynia
On the basis of the above results, we hypothesized that chronic pain derived from nerve injury alters Mammalian target of rapamycin (mTOR) signaling in the insular cortex (IC)
Summary
Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (Merskey and Bogduk, 1994). It is characterized by allodynia, hyperalgesia and spontaneous pain (Jaggi and Singh, 2011). The activation of mTOR complex 1 (mTORC1) regulates protein synthesis by phosphorylating downstream effectors, such as eukaryotic initiation factor 4E binding protein 1 (4EBP1) and p70 ribosomal S6 protein kinase (p70S6K), which influence a wide range of physiological and pathological states (Hay and Sonenberg, 2004; Jaworski and Sheng, 2006; Swiech et al, 2008), including neuropathic, inflammatory and cancer-related pain (Jiménez-Díaz et al, 2008; Géranton et al, 2009; Norsted Gregory et al, 2010). PSD95 may have a role in synaptic plasticity and pain hypersensitivity (Kalia et al, 2008; Kessels and Malinow, 2009; Yasaka et al, 2009; Liu and Salter, 2010; Zhou et al, 2011)
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