This proposal is designed to improve the sensitivity, specificity and validity of animal models of small fiber toxic neuropathy (SFTN) by developing a novel electrophysiological method for the direct, non-invasive assessment of conduction in small diameter axons (A4 and C fibers). Damage to these fibers is a key component of pain, the loss of thermal sensitivity and autonomic deficits induced by neurotoxic exposures (e.g., chemotherapy, industrial or environmental toxicity). Available models for SFTN are limited and the pathophysiology of these abnormalities is poorly understood. The outlined studies will apply a technique of multiple unit recordings, originally developed to measure intracortical conduction in the central nervous system, to the assessment of slow (less than 2.5 m/sec) and asynchronous activity in peripheral nervous system. They also employ techniques of high frequency stimulation to evaluate the hypothesis that small diameter axons are especially vulnerable to deficits in local energy utilization and reserves. The outlined methods will be used to explore SFTN in two distinct animal models of toxic neuropathy: ixabepilone (IXA), a new microtubule-stabilizing agent, and capsaicin (CAP), a local analgesic. IXA impairs both large and small diameter axons and neuropathy is a serious dose-limiting factor of this new anti-cancer treatment. The outlined studies will focus on differences in the onset, pattern, magnitude and degree of recovery of deficits across fiber types, with an emphasis on previously undocumented changes in SFTN. To our knowledge these will be the first comprehensive investigations of animal models of IXA-induced neuropathy. CAP targets substance P-containing axons and evokes an exclusive SFTN. These studies will focus on the development of a non-invasive functional biomarker of activity in the extreme terminal regions on intraepidermal sensory axons. The non-invasive measurement of conduction in small diameter myelinated and unmyelinated axons would provide an alternative and/or complementary measure to the assessment of intraepidermal nerve fiber density (IENFD). In each model, SFTN will be evaluated using surface non-invasive procedures in the most distal segments of both the caudal and digital nerves. Electrophysiological data will be compared to the histopathological changes in a full spectra of nerve fibers (A12, A4 and C fibers) along a distal-to- proximal gradient. If successful, the outlined studies will expand the utility of nerve conduction measures and will provide a new objective and sensitive biomarker for SFTN. The outlined studies will thus greatly improve the utility of existing animal models of a variety of toxic neuropathies, including those associated with chemotherapy, and will provide a new tool for the clinical and preclinical assessment of nerve damage associated with many human diseases including diabetes, AIDS, and genetic neuropathies. PUBLIC HEALTH RELEVANCE: Project Narrative These studies will provide a novel biomarker for toxin-induced or disease-related deficits in the function of small diameter myelinated and unmyelinated axons (A4 and C fibers). Although these axons play a key role in processing pain, thermal sensitivity and autonomic function and are the predominant fiber type in most nerves, they are poorly measured by existing techniques and are therefore understudied. If successful, the outlined studies will greatly improve the utility of existing animal models of a variety of toxic neuropathies, including those associated with chemotherapy, and will provide a new tool for the clinical and preclinical assessment of nerve damage associated with many human diseases including diabetes, AIDS, and genetic neuropathies.
NIH ExPorter
NIH ExPorter