Blocking Mammalian Target of Rapamycin (mTOR) Alleviates Neuropathic Pain Induced by Chemotherapeutic Bortezomib

Abstract

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.

<p>Hyperbaric oxygen relieves neuropathic pain through AKT/TSC2/mTOR pathway activity to induce autophagy</p>

“…mTOR and its downstream pathways were activated in inflammatory pain and neuropathic pain 26,43. Studies show that mTOR inhibitors are promising novel pharmacotherapies for pain management, and are also approved for clinical use 29,43–45. However, in this study, we focused on the upstream pathway of mTOR and HBO treatment.…”

Inhibition of microRNA-155 Reduces Neuropathic Pain During Chemotherapeutic Bortezomib via Engagement of Neuroinflammation

“…On the basis of our previous report (34), "BTZ (0.4 mg/kg body weight; dissolved in saline; Haoran BioTech Co., Shanghai, China) was given intraperitoneally (i.p.) once daily for five consecutive days.…”

“…As described in our previous publication (34), "the samples containing total protein of the L5-L6 dorsal horn tissues were extracted, centrifuged and the supernatants were collected to assess protein concentrations. Then the supernatant (containing 20 µg of protein) were loaded onto gels and electrically transferred to the membrane.…”

“…As described previously in our publications (34,35), "we examined mechanical paw withdrawal threshold (PWT) of rat hindpaw in response to the stimulation of von Frey filaments. In brief, the filaments were bent for 5-10 s in our protocols.…”

“…We used Thermal Place Preference System to execute the thermal place preference test to assess a cold avoidance behavior as described in our previous study (34,35). "We kept the first plate at neutral temperature (25 • C) and the second plate at cold temperature (12 • C).…”