Cancer patients undergoing
paclitaxel infusion usually experience peripheral nerve degeneration and serious
neuropathic pain termed
paclitaxel-induced
peripheral neuropathy (PIPN). However, alterations in the dose or treatment schedule for
paclitaxel do not eliminate PIPN, and no
therapies are available for PIPN, despite numerous studies to uncover the mechanisms underlying the development/maintenance of this condition. Therefore, we aimed to uncover a novel mechanism underlying the pathogenesis of PIPN. Clinical studies suggest that acute over excitation of primary sensory neurons is linked to the pathogenesis of PIPN. We found that
paclitaxel-induced acute hyperexcitability of primary sensory neurons results from the
paclitaxel-induced inhibition of
KCNQ potassium channels (mainly KCNQ2), found abundantly in sensory neurons and axons. We found that repeated application of
XE-991, a specific KCNQ channel blocker, induced PIPN-like alterations in rats, including mechanical
hypersensitivity and degeneration of peripheral nerves, as detected by both morphological and behavioral assays. In contrast, genetic deletion of KCNQ2 from peripheral sensory neurons in mice significantly attenuated the development of
paclitaxel-induced peripheral sensory fiber degeneration and
chronic pain. These findings may lead to a better understanding of the causes of PIPN and provide an impetus for developing new classes of KCNQ activators for its therapeutic treatment.