Involvement of pro-inflammation signal pathway in inhibitory effects of rapamycin on oxaliplatin-induced neuropathic pain

Abstract

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.

Curcumin Alleviates Oxaliplatin-Induced Peripheral Neuropathic Pain through Inhibiting Oxidative Stress-Mediated Activation of NF-κB and Mitigating Inflammation

“…24) In addition, lacking of blood-brain-barrier makes peripheral nervous system more susceptible to the injury of chemotherapeutic accumulation like oxaliplatin, increasing the level of reactive oxygen species (ROS) and destroying the antioxidant-related proteins, and results in the disorder of redox balance in the end. 25,26) Moreover, the increase of ROS could attack the unsaturated fatty acids of nerve cells, then significant high levels of lipid peroxidation arise, resulting in the production of large amounts of MDA, so the level of MDA could be used as an indirect indicator of nerve cells' peroxidation. 27) While activation of antioxidant enzymes (SOD, GSH-Px and CAT) could reflect the elimination of ROS to a certain extent, [28][29][30] Liu and colleagues 31) and his team found that applicated antioxidant enzymes early could alleviate dysfunction of neurons, further confirmed the important role that oxidative stress playing in oxaliplatin-induced neuropathic pain.…”

Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain

“…Oxaliplatin-induced pain has also been shown to be accompanied with the upregulation of PI3K-mTOR and mTOR-mediated signals as well as IL-1β, IL-6, and TNF-α in DRG. As PI3K or mTOR signal was inhibited, mechanical and cold hypersensitivity were attenuated in oxaliplatin treated rats, and the levels of proinflammatory cytokines also decreased [38]. The upregulation of pro-inflammatory cytokines and membrane pro-inflammatory cytokine receptors in the midbrain periaqueductal gray, which has an inhibitory or excitatory control on pain transmission via the rostral ventromedial medulla, projecting to the spinal dorsal horn, of oxaliplatin treated rats is likely to impair the descending inhibitory pathways in regulation of pain transmission and thereby, contribute to the development of neuropathic pain after the administration of chemotherapeutic oxaliplatin [39].…”

The α9α10 Nicotinic Acetylcholine Receptor Antagonist αO-Conotoxin GeXIVA[1,2] Alleviates and Reverses Chemotherapy-Induced Neuropathic Pain

“…Oxaliplatin (T0164, TargetMol) was dissolved in 5% GS to 2 mg/mL and intraperitoneally (IP) injected at a dose of 6 mg/kg to establish the neuropathic pain model [46]. The control group animals received a corresponding volume of 5% GS injection.…”