Jill C. Fehrenbacher, PhD

Injury, inflammation and a number of diseases and/or drug treatments for diseases can alter the function of sensory neurons in the periphery, spinal cord, and in the brain that result in pain or altered sensation in the periphery. The long-term goal of our research is to understand how diseases and drugs can modulate the function of peripheral sensory neurons to underlie clinical neuronal dysfunction. In addition, we also are interested in how sensory neuron function can alter cancer growth and metastasis. Our research spans a wide scope of science, from systems biology to reductionist studies to examine the function of sensory neurons to single-cell RNAseq studies to identify the effects of diseases and drugs on the transcriptome of individual sensory neurons.

With an increase in survival rates for cancer patients, there is a growing concern regarding the potential of cancer treatments, such as the platinum drugs, microtubule targeted agents (taxanes, vinca alkaloids, and epothilones), proteasome inhibitors and immunomodulators, to produce neurotoxicity, which can significantly impair the quality of life in survivors. Of the various side effects of these agents, chemotherapy-induced peripheral neuropathy (CIPN) is of major concern because it occurs frequently, is debilitating, and is sometimes irreversible. There are currently no treatment options to prevent the development or reverse the symptoms of peripheral neuropathy and this is due, at least in part, to a lack of understanding regarding the molecular mechanisms by which chemotherapeutics alter neuronal function. Therefore, a broad focus of my laboratory has been to discern the mechanisms by which chemotherapeutics alter the sensitivity and morphology of sensory neurons.

Other investigators in the field of CIPN have firmly established paradigms by which treatment of animals with chemotherapeutics results in pain symptoms of neuropathy and intraepidermal nerve fiber (IENF) loss, similar to what is observed in patients in the clinic.  However, these animal models provide few opportunities to perform interventional mechanistic studies to elucidate which signaling pathways mediate the effects of chemotherapeutics on neuronal sensitivity and morphology. We started our reductionist studies looking at the effects of the microtubule-stabilizing drug, paclitaxel on sensory neuronal cultures derived from the dorsal root ganglia of rats. We found that inclusion of paclitaxel in the growth medium augmented or reduced the sensitivity of nociceptive sensory neurons that contain the neuropeptide, calcitonin gene-related peptide, dependent upon the concentration of the drug and the duration of exposure.  A relatively low concentration of paclitaxel augments transmitter release, whereas a high concentration can reduce transmitter release. Although these reduced studies are limited to examining a direct role of paclitaxel on sensory neurons and mostly discount the involvement of the immune system, in a very simplistic manner they do recapitulate clinical observations. We hypothesized that paclitaxel-induced increases in neuropeptide release could contribute to a ‘gain of function’ of primary sensory neurons, experienced by patients as mechanical allodynia and tingling, whereas the decreased release of neuropeptides could mediate a ‘loss of function’ of primary sensory neurons. A loss of sensory neuron activity could produce numbness and alter the sensitivity to cold temperatures, either through neuronal crosstalk or via disruption of peripheral blood flow in patients, and therefore mediate cold-induced burning pain in patients. We next utilized this in vitro model to examine whether nerve growth factor (NGF), a growth factor that is known to enhance the sensitivity of sensory neurons and promote neurite growth, could protect against the functional and morphological toxicity of paclitaxel and epothilone. We demonstrated that NGF can affect paclitaxel- or epothilone-induced changes in neuropeptide release but has no effect on paclitaxel- or epothilone-induced changes in neurite length, using a high throughput assay to measure neurite length. These are some of the first data available that interrogate whether changes in neuronal sensitivity are causative for the retraction of neurites or vice versa. Our latest manuscript was inspired by the observations that an acute exposure to paclitaxel activated protein kinase C (PKC). Since an acute activation of PKC results in downregulation of the protein, we examined whether a loss of PKC plays a role to maintain the loss of neuronal sensitivity after chronic exposure to paclitaxel, in vitro. Our work indicates that the conventional PKC isozymes are critical mediators that maintain changes in neuronal sensitivity in nociceptive sensory neurons following chronic exposure to paclitaxel. We showed that chronic treatment with paclitaxel inhibits the activity and membrane localization of active PKC to elicit a reduction in the stimulated release of neuropeptide from nociceptive neurons. These findings provide a starting point to mechanistically understand the effects of chronic exposure to paclitaxel on sensory neuronal function.