Global Inhibition of Reactive Oxygen Species (ROS) Inhibits Paclitaxel-Induced Painful Peripheral Neuropathy

Paclitaxel (Taxol®) is a widely used chemotherapeutic agent that has a major dose limiting side-effect of painful peripheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies. Evidence for mitochondrial dysfunction during paclitaxel-induced pain was previously indicated with the presence of swollen and vacuolated neuronal mitochondria. As mitochondria are a major source of reactive oxygen species (ROS), the aim of this study was to examine whether pharmacological inhibition of ROS could reverse established paclitaxel-induced pain or prevent the development of paclitaxel-induced pain. Using a rat model of paclitaxel-induced pain (intraperitoneal 2 mg/kg paclitaxel on days 0, 2, 4 & 6), the effects of a non-specific ROS scavenger, N-tert-Butyl-α-phenylnitrone (PBN) and a superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were compared. Systemic 100 mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8 g and 15 g stimulation and cold hypersensitivity to plantar acetone application. Daily systemic administration of 50 mg/kg PBN (days −1 to 13) completely prevented mechanical hypersensitivity to von Frey 4 g and 8 g stimulation and significantly attenuated mechanical hypersensitivity to von Frey 15 g. Systemic 100 mg/kg TEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250 mg/kg) systemic TEMPOL significantly inhibited mechanical hypersensitivity to von Frey 8 g & 15 g, but to a lesser extent than PBN. Daily systemic administration of 100 mg/kg TEMPOL (day −1 to 12) did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role in the development and maintenance of paclitaxel-induced pain, but such effects cannot be attributed to superoxide radicals alone

Chemotherapy-induced painful neuropathy:pain-like behaviours in rodent models and their response to commonly used analgesics

PURPOSE OF REVIEW: Chemotherapy-induced painful neuropathy (CIPN) is a major dose-limiting side-effect of several widely used chemotherapeutics. Rodent models of CIPN have been developed using a range of dosing regimens to reproduce pain-like behaviours akin to patient-reported symptoms. This review aims to connect recent evidence-based suggestions for clinical treatment to preclinical data. RECENT FINDINGS: We will discuss CIPN models evoked by systemic administration of taxanes (paclitaxel and docetaxel), platinum-based agents (oxaliplatin and cisplatin), and the proteasome-inhibitor - bortezomib. We present an overview of dosing regimens to produce CIPN models and their phenotype of pain-like behaviours. In addition, we will discuss how potential, clinically-available treatments affect pain-like behaviours in these rodent models, relating those effects to clinical trial data wherever possible. We have focussed on anti-depressants, opioids and gabapentinoids given their broad usage. SUMMARY: This review outlines the latest description of the most-relevant rodent models of CIPN enabling comparison between chemotherapeutics, dosing regimen, rodent strain and gender. Preclinical data supports many of the recent suggestions for clinical management of established CIPN and provides evidence for potential treatments warranting clinical investigation. Continued research using rodent CIPN models will provide much needed understanding of the causal mechanisms of CIPN, leading to new treatments for this major clinical problem

Evoked and ongoing pain-like behaviours in a rat model of paclitaxel-induced peripheral neuropathy

Paclitaxel-induced neuropathic pain is a major dose-limiting side effect of paclitaxel therapy. This study characterises a variety of rat behavioural responses induced by intermittent administration of clinically formulated paclitaxel. 2 mg/kg paclitaxel or equivalent vehicle was administered intraperitoneally on days 0, 2, 4, and 6 to adult male Sprague-Dawley rats. Evoked pain-like behaviours were assessed with von Frey filaments, acetone, or radiant heat application to plantar hind paws to ascertain mechanical, cold, or heat sensitivity, respectively. Motor coordination was evaluated using an accelerating RotaRod apparatus. Ongoing pain-like behaviour was assessed via spontaneous burrowing and nocturnal wheel running. Mechanical and cold hypersensitivity developed after a delayed onset, peaked approximately on day 28, and persisted for several months. Heat sensitivity and motor coordination were unaltered in paclitaxel-treated rats. Spontaneous burrowing behaviour and nocturnal wheel running were significantly impaired on day 28, but not on day 7, indicating ongoing pain-like behaviour, rather than acute drug toxicity. This study comprehensively characterises a rat model of paclitaxel-induced peripheral neuropathy, providing the first evidence for ongoing pain-like behaviour, which occurs in parallel with maximal mechanical/cold hypersensitivity. We hope that this new data improve the face validity of rat models to better reflect patient-reported pain symptoms, aiding translation of new treatments to the clinic

Evoked and Ongoing Pain-Like Behaviours in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy

Paclitaxel-induced neuropathic pain is a major dose-limiting side effect of paclitaxel therapy. This study characterises a variety of rat behavioural responses induced by intermittent administration of clinically formulated paclitaxel. 2 mg/kg paclitaxel or equivalent vehicle was administered intraperitoneally on days 0, 2, 4, and 6 to adult male Sprague-Dawley rats. Evoked pain-like behaviours were assessed with von Frey filaments, acetone, or radiant heat application to plantar hind paws to ascertain mechanical, cold, or heat sensitivity, respectively. Motor coordination was evaluated using an accelerating RotaRod apparatus. Ongoing pain-like behaviour was assessed via spontaneous burrowing and nocturnal wheel running. Mechanical and cold hypersensitivity developed after a delayed onset, peaked approximately on day 28, and persisted for several months. Heat sensitivity and motor coordination were unaltered in paclitaxel-treated rats. Spontaneous burrowing behaviour and nocturnal wheel running were significantly impaired on day 28, but not on day 7, indicating ongoing pain-like behaviour, rather than acute drug toxicity. This study comprehensively characterises a rat model of paclitaxel-induced peripheral neuropathy, providing the first evidence for ongoing pain-like behaviour, which occurs in parallel with maximal mechanical/cold hypersensitivity. We hope that this new data improve the face validity of rat models to better reflect patient-reported pain symptoms, aiding translation of new treatments to the clinic

New advances in musculoskeletal pain

Non-malignant musculoskeletal pain is the most common clinical symptom that causes patients to seek medical attention and is a major cause of disability in the world. Musculoskeletal pain can arise from a variety of common conditions including osteoarthritis, rheumatoid arthritis, osteoporosis, surgery, low back pain and bone fracture. A major problem in designing new therapies to treat musculoskeletal pain is that the underlying mechanisms driving musculoskeletal pain are not well understood. This lack of knowledge is largely due to the scarcity of animal models that closely mirror the human condition which would allow the development of a mechanistic understanding and novel therapies to treat this pain. To begin to develop a mechanism-based understanding of the factors involved in generating musculoskeletal pain, in this review we present recent advances in preclinical models of osteoarthritis, post-surgical pain and bone fracture pain. The models discussed appear to offer an attractive platform for understanding the factors that drive this pain and the preclinical screening of novel therapies to treat musculoskeletal pain. Developing both an understanding of the mechanisms that drive persistent musculoskeletal pain and novel mechanism-based therapies to treat these unique pain states would address a major unmet clinical need and have significant clinical, economic and societal benefits

Effect of TEMPOL on established paclitaxel-induced mechanical hypersensitivity.

<p>A–C show the effect of systemic 100 mg/kg TEMPOL, 250 mg/kg TEMPOL or vehicle administration on behavioural responses to von Frey 4 g, 8 g and 15 g stimulation, respectively, on day 27 following paclitaxel initiation. Graphs show the mean ± SEM of response frequency to mechanical stimulation after paclitaxel but before TEMPOL/vehicle injection (Post Pacl./Pre inj.), and then 1, 3 and 24 hours following TEMPOL/vehicle administration. *p<0:05; one-way ANOVA with Tukey-Kramer post hoc analysis, n = 8 per group.</p

Effect of prophylactic TEMPOL on the development of paclitaxel-induced mechanical hypersensitivity.

<p>Systemic 100 mg/kg TEMPOL or vehicle was administered once daily for 14 consecutive days (day −1 through to day 12) with systemic paclitaxel administration occurring on days 0, 2, 4 & 6. Graphs show the mean ± SEM of the response frequency to mechanical stimulation by A) von Frey 4 g, B) von Frey 8 g and C) von Frey 15 g before paclitaxel (Pre Pacl.) and up to day 45 post-paclitaxel initiation. *p<0.05; one-way, repeated measures ANOVA with Dunnett's post hoc analysis compared to pre-paclitaxel readings, n = 9 per group. NB: The asterisks indicate the occurrence of significant paclitaxel-induced mechanical hypersensitivity.</p