Effects of rapamycin on mTOR signaling in the insular cortex of neuropathic rats

Abstract

Injury of peripheral nerves can trigger neuropathic pain, producing allodynia and hyperalgesia via peripheral and central sensitization. Neuropathic pain is related to physiological changes in the primary afferent nerves, including spinal cord and brain. Recent studies have focused on the role of the insular cortex in neuropathic pain. Because the insular cortex is thought to store pain-related memories, translational regulation in this structure may reveal novel targets for controlling chronic pain. In neurons, many proteins that are involved in the inducement of synaptic activity and the expression of synaptic plasticity are converged at synapses especially. Signaling via mammalian target of rapamycin (mTOR), which is known to control mRNA translation and influence synaptic plasticity, may be involved in the development of chronic pain. The activity of mTOR and its downstream effectors have been detected in peripheral and central regions including pain transmission. mTOR has been studied at the spinal level in neuropathic pain, but its role in the insular cortex 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 mTOR, in the insular cortex of rats with neuropathic pain. Mechanical allodynia was assessed in adult male Sprague-Dawley rats after neuropathic surgery and following microinjections of rapamycin in the insular cortex on post-operative days 3 and 7. To evaluate the effective pain prevention of pre-administration with rapamycin in the insular cortex, the animals were microinjected rapamycin into the insular cortex before nerve injury. Rapamycin reduced mechanical allodynia and downregulated the expression of mTOR signaling pathway, postsynaptic density protein 95 and N-methyl-D-aspartate receptor, thereby inhibiting neuropathic pain-induced synaptic plasticity. Finally, pre-microinjection of rapamycin effectively alleviated development mechanical allodynia but failed to the down regulated mTOR signaling pathway. These findings suggest that mTOR signaling in the insular cortex may be a critical molecular mechanism modulating neuropathic pain.