Rapamycin alleviates proinflammatory cytokines and nociceptive behavior induced by chemotherapeutic paclitaxel.

Background/Aims: Paclitaxel is largely used as a chemotherapeutic agent for the treatment of several types of cancers. However, one of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy. The purposes of this study were to examine (1) the effects of blocking mammalian target of rapamycin (mTOR) on mechanical and thermal hypersensitivity evoked by paclitaxel; and (2) the underlying mechanisms responsible for the role of mTOR in regulating paclitaxel-induced neuropathic pain. Methods: Behavioral test was performed to determine mechanical and thermal sensitivity in rats. ELISA was used to examine the levels of proinflammatory cytokines (PICs including IL-1 beta, IL-6, and TNF-alpha) and substance P and calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DGR); and Western blot analysis was used to examine expression of mTOR signal pathway. Results: Paclitaxel increased mechanical and thermal sensitivity as compared with vehicle control animals (P vs. controls). Paclitaxel also amplified the expression of p-mTOR, mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4E-binding protein 1 (p-4E-BP1) in the DRG. Blocking mTOR using rapamycin attenuated peripheral painful neuropathy observed in paclitaxel rats (P vs. without rapamycin). This inhibitory effect was accompanied with decreases of IL-1 beta, IL-6, and TNF-alpha as well as substance P and CGRP. In addition, inhibition of phosphatidylinositide 3-kinase (p-PI3K) attenuated expression of p-mTOR and PICs/substance P/CGRP in paclitaxel rats and this further attenuated mechanical and thermal hypersensitivity. Conclusions: The data revealed specific signaling pathways leading to paclitaxel-induced peripheral neuropathic pain, including the activation of PI3K-mTOR, PIC signal, and substance P and CGRP. 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 paclitaxel.