Chemotherapy is often accompanied by neuropathic sensory disorders that can limit or end treatment and cause long-term disability. Current research supports axon degeneration and hyperexcitability as underlying mechanisms. However, our recent research reveals an additional, absolutely novel mechanism having the potential to account for loss of patient function in chemotherapy-related neuropathy. We obtained in vivo electrophysiological measures which showed functional impairment of neuronal signaling from sensory and motor neurons in rats several weeks after receiving a clinically-relevant regimen of oxaliplatin (OX) chemotherapy. Hypo-excitability was consistently expressed as conspicuous failure to sustain firing in response to fixed levels of stimulation. The specificity of this defect, which leaves transient firing unaffected, suggests that OX treatment may impair sodium persistent inward currents (NaPIC) in sensory and motor neurons. Recent findings published in our lab promote this notion by showing that pharmacological block of NaPIC mimics the effect of OX on sustained firing. While our findings isolate chronic effects of chemotherapy on neuronal excitability, there is no chemotherapy without cancer. Cancer and OX therapy may act synergistically on common signaling pathways (e.g. oxidative and inflammatory) to produce neuronal hypo- excitability. The possibility of an interaction between cancer and OX therapy gains excitement from our preliminary reports that discovered sensory and motor neuron hypo-excitability is significantly amplified in rats with colorectal cancer. Here we propose incisive tests of our working hypothesis that OX treatment chronically impairs static neuronal signaling by reducing NaPIC in a rat model of cancer. We will measure the firing behavior of sensory and motor neurons via in vivo electrophysiological studies of cancer rats treated with OX, in order to achieve the following four specific aims: 1) test the hypothesis that interactions with cancer-related processes exacerbate chemotherapy-induced hypo-excitability in sensory and motor neurons; 2) test the hypothesis that chronic defects in repetitive firing by motor neurons result from an OX-induced decrease in persistent inward current; 3) develop therapy that normalizes firing of sensory and motor neurons in rats treated for cancer with OX; 4) identify factors related to the development of hypo-excitability induced by OX in a rat model of colorectal cancer. Successful accomplishment of these studies will: 1) determine for the first time in the CIPN field, of the extent to which chronic deficits in neuronal excitability arise from OX therapy, colorectal cancer, and their combination; 2) identify biophysical mechanisms underlying firing deficits of a CNS neuron after OX treatment; 3) develop pre-clinically a viable therapy for rescuing neurons from OX-induced firing deficits; 4) take the first step forward in understanding the pathogenesis of OX-induced hypo-excitability by relating its development and underlying biophysics to changes in gene expression of sensory and MNs.
Our work could potentially lead to a targeted therapy that relieves the chronic disability caused by commonly used anticancer drugs. Restoring normal firing to sensory and motor neurons could improve sensation and mobility in patients who receive chemotherapy, allow therapy to be completed in more cases, and greatly reduce long-term disability.
