Paclitaxel-induced Mechanical Hypersensitivity Research Articles

4. Lewis and Sprague Dawley, but not Fischer 344 rats, exhibit sustained paclitaxel-induced mechanical hypersensitivity

Paclitaxel (PAC), a commonly prescribed chemotherapy, is associated with a painful, dose-limiting neuropathy that can persist beyond treatment. The role of hypothalamic–pituitary–adrenal (HPA) axis stress responsivity in PAC-induced mechanical hypersensitivity is unknown. Adult male and female Lewis ( n = 26), Sprague–Dawley ( n = 29) and Fischer 344 ( n = 27) rats met baseline paw withdrawal threshold (PWT, >10 g) via von Frey Hair (VFH) testing. Rats received intraperitoneal paclitaxel (1 mg/kg) or vehicle on days 1, 3, 5, 7 (8–14 drug break); this cycle was repeated twice (days 15–28, and 29–42) to model a clinical chemotherapy protocol. VFH testing occurred through day 42. We ran repeated measures ANOVA to ascertain the accumulative (post 4, 8, and 12 mg/kg), and sustained (7 days post 4, 8, and 12 mg/kg) effects of PAC on mechanical hypersensitivity. After each cycle, PAC ( F (1) = 50.78, p < 0.01) and PAC by strain ( F (2) = 4.75, p = 0.01; LEW and SD) were associated with greater mechanical hypersensitivity. After each drug break, PAC ( F (1) = 9.53, p < 0.01), PAC by strain (9i (2) = 7.35, p < 0.01; LEW and SD), and sex by strain ( F (2) = 3.34, p = 0.04; LEW females) were associated with greater mechanical hypersensitivity. HPA axis hyperresponsivity was associated with reduced PAC-induced mechanical hypersensitivity and greater ability to recover to baseline PWT. Further work is needed to determine the specific mechanism(s) involved.

TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism

Paclitaxel produces a sensory neuropathy, characterized by mechanical and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel has been reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mechanical allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mechanical and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mechanical allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the two antagonists. The reduced paclitaxel-evoked mechanical allodynia, observed in TRPA1-deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC-030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, observed in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical formation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mechanical allodynia. Cold allodynia is, however, entirely dependent on TRPA1.

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.

Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain

Paclitaxel chemotherapy is limited by a long-lasting painful neuropathy that lacks an effective therapy. In this study, we tested the hypothesis that paclitaxel may release mast cell tryptase, which activates protease-activated receptor 2 (PAR2) and, subsequently, protein kinases A and C, resulting in mechanical and thermal (both heat and cold) hypersensitivity. Correlating with the development of neuropathy after repeated administration of paclitaxel, mast cell tryptase activity was found to be increased in the spinal cord, dorsal root ganglia, and peripheral tissues in mice. FSLLRY-amide, a selective PAR2 antagonist, blocked paclitaxel-induced neuropathic pain behaviors in a dose- and time-dependent manner. In addition, blocking downstream signaling pathways of PAR2, including phospholipase C (PLC), protein kinase A (PKA), and protein kinase Cε (PKC), effectively attenuated paclitaxel-induced mechanical, heat, or cold hypersensitivity. Furthermore, sensitized pain response was selectively inhibited by antagonists of transient receptor potential (TRP) V1, TRPV4, or TRPA1. These results revealed specific cellular signaling pathways leading to paclitaxel-induced neuropathy, including the activation of PAR2 and downstream enzymes PLC, PKCε, and PKA and resultant sensitization of TRPV1, TRPV4, and TRPA1. Targeting one or more of these signaling molecules may present new opportunities for the treatment of paclitaxel-induced neuropathy.