Phenyl N -tert-butylnitrone, a Free Radical Scavenger, Reduces Mechanical Allodynia in Chemotherapy-induced Neuropathic Pain in Rats

Abstract

Background: Paclitaxel is a widely used chemotherapeutic drug for breast and ovarian cancer. Unfortunately, it induces neuropathic pain, which is a dose-limiting side effect. Free radicals have been implicated in many neurodegenerative diseases. The current study tests the hypothesis that a free radical scavenger plays an important role in reducing chemotherapy-induced neuropathic pain. Methods: Neuropathic pain was induced by intraperitoneal injection of paclitaxel (2 mg/kg) on four alternate days (days 0, 2, 4, and 6) in male Spraue-Dawley rats. Phenyl N-tert-butylnitrone (PBN), a free radical scavenger, was administered intraperitoneally as a single dose or multiple doses before or after injury. Mechanical allodynia was measured by using von Frey filaments. Results: The administration of paclitaxel induced mechanical allodynia, which began to manifest on days 7-10, peaked within 2 weeks, and plateaued for at least 2 months after the first paclitaxel injection. A single injection or multiple intraperitoneal injections of PBN ameliorated paclitaxel-induced pain behaviors in a dose-dependent manner. Further, multiple administrations of PBN starting on day 7 through day 15 after the first injection of paclitaxel completely prevented the development of mechanical allodynia. However, an intraperitoneal administration of PBN for 8 days starting with the first paclitaxel injection did not prevent the development of pain behavior.Conclusions: This study clearly shows that PBN alleviated mechanical allodynia induced by paclitaxel in rats. Furthermore, our data show that PBN given on days 7 through 15 after the first paclitaxel injection prevented the development of chemotherapy-induced neuropathic pain. This clearly has a clinical implication.

The Contribution of Mitochondria to Sensory Processing and Pain

“…Phenyl N-tert-butylnitrone (PBN), a nonspecific ROS scavenger, reversed established paclitaxel-induced mechanical hypersensitivity 49,50 and paclitaxel-induced cold allodynia. 50 PBN also markedly inhibited the development of paclitaxel-induced mechanical hypersensitivity, when administered in a prophylactic paradigm which that encompasses the week immediately following paclitaxel administration.…”

Mechanisms Involved in the Development of Chemotherapy-Induced Neuropathy

“…As mentioned previously, mitochondrial-released ROS can then activate apoptotic and proinflammatory pathways, contributing to chronic CIPN. Further evidence for a role of ROS in CIPN was the finding that administration of ROS scavengers alleviates paclitaxel-induced mechanical hyperalgesia [84,85]. Peroxynitrite, a powerful oxidant and nitrating agent produced by ROS, has been proposed as a potential therapeutic target for ameliorating CIPN based on translational work in rodents [86].…”

AMPKα1 knockout enhances nociceptive behaviors and spinal glutamatergic synaptic activities via production of reactive oxygen species in the spinal dorsal horn

“…ROS have functions in cellular signaling and regulation [36-38] and have shown to be master signaling molecules controlling inflammatory signaling cascades. ROS plays an important role in the genesis of many pathological pain conditions [39, 40], including neuropathic pain induced by nerve injury [41, 42] or chemotherapy [43], and inflammatory pain induced by carrageenan [44], and morphine-tolerance [45-47]. Currently, it is not fully understood about endogenous molecular signaling pathways regulating the production of ROS and the impacts of ROS on synaptic activities at the spinal dorsal horn.…”