Abstract
Previous studies have shown an increase of insulin-like growth factor-2 (IGF2) in animal models of neuropathic pain. We aimed to examine the hypothesis that reducing the expression of IGF2 using intrathecal IGF2 small-interfering RNA (siRNA) would attenuate the development of neuropathic pain in rats after spared nerve injury (SNI). Male Wistar rats were divided into three groups: sham-operated group, in which surgery was performed to cut the muscles without injuring the nerves; SNI group, in which SNI surgery was performed to sever the nerves; and SNI + siRNA IGF2 group, in which SNI surgery was performed, and IGF2-siRNA was administered intrathecally 1 day after SNI. The rats were assessed for mechanical allodynia and cold allodynia 1 day before surgery (baseline), and at 2, 4, 6, 8, and 10 days after siRNA treatment. The rat spinal cord was collected for quantitative polymerase chain reaction and western blot analysis. Compared with the SNI group, rats that received IGF2 siRNA showed a significantly increased SNI-induced paw-withdrawal threshold to metal filament stimulation from Day 4 to Day 10 after SNI surgery. IGF2 siRNA significantly decreased the response duration from the acetone test from Day 2 to Day 10 following SNI surgery. SNI increased IGF2 mRNA expression on Day 2 and increased IGF2 protein expression on Day 8 and Day 10 in the spinal cord of the SNI rats. However, the above-mentioned effects of IGF2 mRNA and protein expression were significantly inhibited in the SNI + IGF2 siRNA group. We demonstrated that intrathecal administration of IGF2 siRNA provided significant inhibition of SNI-induced neuropathic pain via inhibition of IGF2 expression in the spinal cord. The analgesic effect lasted for 10 days. Further exploration of intrathecal IGF2 siRNA administration as a potential therapeutic strategy for neuropathic pain is warranted.
Highlights
Neuropathic pain is a major public health concern that is defined by the International Association for the Study of Pain (IASP) as ‘pain caused by a lesion or disease of the somatosensory nervous system’ [1]
In our previous study that investigated the impact of pulsed radiofrequency (PRF) on the modulation of pain-regulatory genes after spared nerve injury (SNI) in rats, we demonstrated that PRF treatment significantly inhibited the development of neuropathic pain and down-regulated insulin-like growth factor-2 (IGF2) expression in the dorsal horn of the rat spinal cord [8], suggesting that inhibiting IGF2 expression in the rat spinal cord might play a role in alleviating neuropathic pain
Male Wistar rats were divided into three groups as follows: (1) sham-operated group: surgery was performed to cut the muscles without injuring the nerves; (2) SNI group: SNI surgery was performed to sever the nerves; (3) SNI + small-interfering RNA (siRNA) IGF2 group: SNI surgery was performed, and IGF2-siRNA was administered by intrathecal injection once a day after SNI
Summary
Neuropathic pain is a major public health concern that is defined by the International Association for the Study of Pain (IASP) as ‘pain caused by a lesion or disease of the somatosensory nervous system’ [1]. It is a clinical description which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria [2]. The functions of siRNA include gene-silencing process targeting and degrading specific mRNA molecules, resulting in the degradation of mRNA It can regulate multiple important biological processes associated with the onset and progression of inflammation [10]. We aimed to test the hypothesis that IGF2 siRNAs alleviate neuropathic pain, by verifying its effects on an SNI rat model
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