(384) Targeting KCNQ channels to prevent and ameliorate paclitaxel-induced peripheral neuropathy

Abstract

Paclitaxel is routinely used to treat breast cancer patients. However, paclitaxel induces toxic effects, among which peripheral sensory neuropathy accompanied by neuropathic pain is particularly severe and is often a limiting factor in treatment. Several pharmacological interventions have been proposed for paclitaxel-induced chronic pain treatment, but none have been shown to be both widely effective and without serious side effects. Recent studies indicated that the development and maintenance of peripheral neuropathy including associated pain is driven by intense, long-lasting excitation of neurons exposed to paclitaxel. Reducing this excessive excitation may reverse or prevent paclitaxel-induced peripheral neuropathy. K+ channels (Kv7 or KCNQ/M channels) are abundantly expressed in primary sensory neurons to control excitability. We hypothesized that KCNQ/Kv7 channels are a potential therapeutic target to ameliorate and prevent neuropathic pain associated with PIPN by reducing the hyperexcitability of primary sensory neurons. Retigabine, a specific opener of KCNQ channels, was used to test if increasing KCNQ channel activity would reverse or prevent paclitaxel-induced peripheral neuropathy including associated neuropathic pain. Paclitaxel was delivered to tumor-free adult rats and then retigabine was applied to paclitaxel-treated rats 2 weeks later to determine whether retigabine can attenuate established chronic neuropathic pain. Remarkably, retigabine significantly attenuated mechanical hypersensitivity induced by paclitaxel. We also applied retigabine for 10 days during paclitaxel treatment to see if it reduces the development of paclitaxel-induced peripheral neuropathy (PIPN) and associated pain. Retigabine plus paclitaxel treatment resulted in significantly higher mechanical thresholds compared to vehicle plus paclitaxel treatment, assessed 2 weeks after the end of combined treatment. Furthermore, IENF density was reduced by 50% in rats that had received vehicle plus paclitaxel compared to rats co-treated with retigabine and paclitaxel. Our data suggest that KCNQ/Kv7 channels are a potential therapeutic target to ameliorate and prevent neuropathic pain associated with PIPN. Paclitaxel is routinely used to treat breast cancer patients. However, paclitaxel induces toxic effects, among which peripheral sensory neuropathy accompanied by neuropathic pain is particularly severe and is often a limiting factor in treatment. Several pharmacological interventions have been proposed for paclitaxel-induced chronic pain treatment, but none have been shown to be both widely effective and without serious side effects. Recent studies indicated that the development and maintenance of peripheral neuropathy including associated pain is driven by intense, long-lasting excitation of neurons exposed to paclitaxel. Reducing this excessive excitation may reverse or prevent paclitaxel-induced peripheral neuropathy. K+ channels (Kv7 or KCNQ/M channels) are abundantly expressed in primary sensory neurons to control excitability. We hypothesized that KCNQ/Kv7 channels are a potential therapeutic target to ameliorate and prevent neuropathic pain associated with PIPN by reducing the hyperexcitability of primary sensory neurons. Retigabine, a specific opener of KCNQ channels, was used to test if increasing KCNQ channel activity would reverse or prevent paclitaxel-induced peripheral neuropathy including associated neuropathic pain. Paclitaxel was delivered to tumor-free adult rats and then retigabine was applied to paclitaxel-treated rats 2 weeks later to determine whether retigabine can attenuate established chronic neuropathic pain. Remarkably, retigabine significantly attenuated mechanical hypersensitivity induced by paclitaxel. We also applied retigabine for 10 days during paclitaxel treatment to see if it reduces the development of paclitaxel-induced peripheral neuropathy (PIPN) and associated pain. Retigabine plus paclitaxel treatment resulted in significantly higher mechanical thresholds compared to vehicle plus paclitaxel treatment, assessed 2 weeks after the end of combined treatment. Furthermore, IENF density was reduced by 50% in rats that had received vehicle plus paclitaxel compared to rats co-treated with retigabine and paclitaxel. Our data suggest that KCNQ/Kv7 channels are a potential therapeutic target to ameliorate and prevent neuropathic pain associated with PIPN.