As a chemotherapeutic agent, bortezomib (BTZ) is used for the treatment of multiple myeloma with adverse effect of painful peripheral neuropathy. Our current study was to determine the inhibitory effects of blocking microRNA-155 (miR-155) signal on BTZ-induced neuropathic pain and the underlying mechanisms. We employed real time RT-PCR and western blot analysis to examine the miR-155 and expression of pro − inflammatory tumor necrosis factor-α receptor (TNFR1) in the dorsal horn of the spinal cord. Its downstream signals p38-MAPK and JNK and transient receptor potential ankyrin 1 (TRPA1) were also determined. Mechanical pain and cold sensitivity were assessed by behavioral test. In result, inhibition of miR-155 significantly attenuated mechanical allodynia and thermal hyperalgesia in BTZ rats, which was accompanied with decreasing expression of TNFR1, p38-MAPK, JNK, and TRPA1. In contrast, miRNA-155 mimics amplified TNFR1-TRPA1 pathway and augmented mechanical pain and cold sensitivity. In addition, mechanical and thermal hypersensitivity induced by miRNA-155 mimics were attenuated after blocking TNFR1, p38-MAPK, JNK, and TRPA1. Overall, we show the key role of miR-155 in modifying BTZ-induced neuropathic pain through TNFR1-TRPA1 pathway, suggesting that miR-155 is a potential target in preventing neuropathic pain development during intervention of BTZ.

Background/Aims: Bortezomib (BTZ) is largely used as a chemotherapeutic agent for the treatment of cancer. However, one of the significant limiting complications of BTZ is painful peripheral neuropathy during BTZ therapy. Drugs preventing and/or treating the painful symptoms induced by BTZ are lacking since the underlying mechanisms leading to neuropathic pain remain largely unclear. The purposes of this study were to examine 1) the effects of blocking mammalian target of rapamycin (mTOR) on mechanical pain and cold hypersensitivity evoked by BTZ and 2) the underlying mechanisms responsible for the role of mTOR in regulating BTZ-induced neuropathic pain. Methods: Behavioral test was performed to determine mechanical pain and cold sensitivity in a rat model. Western blot analysis and ELISA were used to examine expression of mTOR and phosphatidylinositide 3-kinase (p-PI3K) signals, and the levels of substance P and calcitonin gene-related peptide (CGRP). Results: Systemic injection of BTZ significantly increased mechanical pain and cold sensitivity as compared with control animals (P<0.05 vs. control rats). The expression of p-mTOR, mTORmediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4E-binding protein 4 (p-4E-BP1) as well as p-PI3K was amplified in the dorsal horn of spinal cord of BTZ rats as compared with control rats. Blocking mTOR by intrathecal infusion of rapamycin attenuated mechanical pain and cold hypersensitivity. Blocking PI3K signal also attenuated activities of mTOR, which was accompanied with decreasing neuropathic pain. Inhibition of either mTOR or PI3K blunted enhancement of the spinal substance P and CGRP in BTZ rats. Conclusions: The data for the first time revealed specific signaling pathways leading to BTZ-induced peripheral neuropathic pain, including the activation of mTOR and PI3K. Inhibition of these signal pathways alleviates pain. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of peripheral painful neuropathy observed during chemotherapeutic application of BTZ.

BackgroundOxaliplatin is a third-generation chemotherapeutic agent that is commonly used to treat metastatic digestive tumors; however, one of the main limiting complications of oxaliplatin is painful peripheral neuropathy. The purpose of this study was to examine the underlying mechanisms by which mammalian target of rapamycin (mTOR) and its signal are responsible for oxaliplatin-evoked neuropathic pain.MethodsNeuropathic pain was induced by intraperitoneal injection of oxaliplatin in rats. ELISA and Western blot analysis were used to examine the levels of pro-inflammatory cytokines (including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α) and the expression of mTOR signal pathway.ResultsOxaliplatin increased mechanical and cold sensitivity as compared with control animals (P < 0.05 vs. control rats). Oxaliplatin also amplified the expression of p-mTOR and mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 and 4E-binding protein 1 in the lumbar dorsal root ganglion. Blocking mTOR using rapamycin attenuated peripheral painful neuropathy observed in oxaliplatin rats (P < 0.05 vs. vehicle control). This inhibitory effect was accompanied with decreases of IL-1β, IL-6, and TNF-α. In addition, inhibition of phosphatidylinositide 3-kinase (p-PI3K) attenuated the expression of p-mTOR and the levels of pro-inflammatory cytokines in oxaliplatin rats, and this further attenuated mechanical and cold hypersensitivity.ConclusionsThe data revealed specific signaling pathways leading to oxaliplatin-induced peripheral neuropathic pain, including the activation of PI3K-mTOR and pro-inflammatory cytokine signal. Inhibition of these pathways alleviates neuropathic pain. Targeting one or more of these molecular mediators may present new opportunities for treatment and management of neuropathic pain observed during chemotherapeutic application of oxaliplatin.

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This study investigated the protective effect ofgastrodin on cell apoptosis in rats hippocampus tissues induced by desflurane to explore its mechanism. A total of 36 rats were randomly divided into three groups: Blank control group (C group, n=12), desflurane anesthesia group (DF group, n=12) and gastrodin treatment group (GT group, n=12). Rats in DF group were treated with anesthesia using desflurane. Rats in GT group were treated with gavage using gastrodin and the same treatment as DF group. After the experiment, novel object recognition test and water maze test were performed. The hippocampus tissues were taken from the rat after the behavioral experiment; then the number of apoptotic cells was detected using the terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling (TUNEL) kit, and the mRNA and protein expression levels of p38 and interleukin-1 (IL-1) were detected via semi-quantitative polymerase chain reaction (PCR) and western blot analysis. After the desflurane anesthesia, novel object recognition showed that compared with that in DF group, the exploration capacity of novel objects in GT group was increased (P<0.01). The water maze test showed that the escape latencies in DF group, T1 in GT group was significantly shortened, but T2 was significantly prolonged (P<0.01). TUNEL assay showed that the number of apoptotic cells in hippocampus tissues in GT group was significantly fewer than that in group DF (P<0.01). Semi-quantitative PCR and western blot analysis showed that the expression levels of p38 and IL-1β in GT group were lower than those in DF group (P<0.01). The results show that gastrodin has a protective effect on the apoptosis of hippocampus cells of rats induced by desflurane. Its protection mechanism may be realized through decreasing the increased p38 and IL-1β expression levels induced by desflurane, thus blocking the p38 mitogen-activated protein kinase (p38 MAPK) pathway.