Tempol Ameliorates and Prevents Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain.

Hee Kee Kim,Salahadin Abdi,Seon-Hee Hwang

doi:10.3389/fphar.2016.00532

Abstract

Chemotherapy-induced neuropathic pain is difficult to treat and prevent. Tempol decreases cellular superoxide radical levels and oxidative stress. The aims of our study were to investigate the analgesic and preventive effects of tempol on paclitaxel-induced neuropathic pain in rats and to identify the associated mechanisms of action. Neuropathic pain was induced with intraperitoneally injected paclitaxel on four alternate days in male Sprague–Dawley rats. Tempol was administered systemically as a single injection and a continuous infusion before or after the injection of paclitaxel. The mechanical threshold for allodynia, protein levels, and free radical levels were measured using von Frey filaments, Western blotting, and live cell imaging, respectively. After the rats developed neuropathic pain behavior, a single intraperitoneal injection and continuous infusion of tempol ameliorated paclitaxel-induced mechanical allodynia. Systemic infusion of tempol in the early phase of the development of pain behavior prevented the development of paclitaxel-induced pain behavior. Paclitaxel increased the levels of phosphorylated protein kinase C, phosphorylated nuclear factor κB, phosphodiesterase 4D (PDE4D), IL-1β, and monocyte chemoattractant protein-1 in the lumbar dorsal root ganglia; however, tempol decreased these levels. Paclitaxel also increased superoxide levels in a culture of primary dorsal root ganglion cells and tempol decreased these levels. In conclusion, tempol alleviates and prevents chemotherapy-induced neuropathic pain in rats by reducing the levels of inflammatory cytokines and free radicals in dorsal root ganglia.

Highlights

Chemotherapeutic agents, including taxanes, vinca alkaloids, platinum agents, and others, produce peripheral pain in the distal extremities in a symmetrical glove and stocking distribution (Yazdani and Abdi, 2014)
All rats treated with tempol without paclitaxel showed normal behavior including no sedation, no pain behavior, and normal increase in body weight
The treatment beginning on day 6 completely prevented further development of pain behavior for 40 days in paradigm II (Figure 3B). These data indicate that tempol prevented the development of paclitaxel-induced neuropathic pain (PINP) when given during the development phase of mechanical hyperalgesia

Summary

Introduction

Chemotherapeutic agents, including taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vincristine, vinblastine), platinum agents (e.g., cisplatin, carboplatin, oxaliplatin), and others (e.g., thalidomide, bortezomib, lenalidomide), produce peripheral pain in the distal extremities in a symmetrical glove and stocking distribution (Yazdani and Abdi, 2014). Chemotherapy-induced neuropathic pain is a dose-limiting adverse effect that can take place at any time during the course of the treatment or even after its termination (Windebank and Grisold, 2008). This neuropathy can significantly decrease the overall quality of life in cancer patients (Mols et al, 2014; Rivera and Cianfrocca, 2015). It has been reported that glutamine, glutathione, N-acetylcysteine, oxcarbazepine, and xaliproden did not prevent chemotherapy-induced neuropathy (Wolf et al, 2008). Currently, no effective medications are available to treat or prevent neuropathic pain (Lee and Swain, 2006; Wolf et al, 2008; Hershman et al, 2014) and new alternatives need to be explored

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