The principal investigator, Rosemary C. Polomano, PhD, RN, intends to pursue a career as an independent, clinical and laboratory investigator in biobehavioral pain research in a health system with an academic appointment in a school of nursing and medicine. Intensive laboratory training combined with academic study in neuroscience will enable the principal investigator to examine and better explain the neurophysiological basis for pain associated with paclitaxel neurotoxicity. The primary aim of this investigation is to develop a painful neurotoxicity model appropriate for human disease, and to effectively translate the findings to human experiences. Painful manifestations from paclitaxel-induced neuropathy will be measured by abnormalities in responses to thermal- (heat and cold) and mechano- (touch and pressure) stimuli in the rats' hind paws and tails that result from damage to the small primary or sensory afferent fibers. This model will advance the development and testing of possible strategies for pain prevention and control, thus increasing the usefulness of this highly effective antineoplastic drug. Graded dosing schedules of paclitaxel or a control vehicle will be administered to 280 male Sprague-Dawley rats in order to find one that produces the greatest degree of a painful peripheral neuropathy, without reaching the threshold for damage to motor fibers or systemic toxicity. Specifically, this investigation will 1) demonstrate and quantify the onset, duration and severity of painful peripheral neuropathy in rats treated with intraperitoneal paclitaxel by measuring behavioral responses (i.e., thermal- and mechano-hyperalgesia and cold- and mechano- allodynia) in the hind paw and tail and motor coordination, and electrophysiological changes in the hind leg nerves following sequential doses, 2) compare differences in the severity of pain- evoked responses for the four paclitaxel dosing schedules to determine if single-dose intensity of cumulative (total) dose produces the greatest sensory abnormalities, and 3) correlate sensory abnormalities in small myelinated (A-delta) and unmyelinated (C-) fibers to the presence and severity of anatomical changes in the nerves and serum peak levels of paclitaxel. Chemotherapy-induced peripheral neurotoxicity is a problem that will only worsen as advances in granulocyte-colony stimulating factor now permit more aggressive therapy with potentially neurotoxic agents. Greater attention has been placed on understanding peripheral sensory and motor neuropathies associated with chemotherapy because these conditions compromise quality of life. As concerns over quality of life and the long- term effects of cancer treatment among survivors grow and clinicians struggle with ways to manage these effects, animal models will become a vital line of inquiry into the scientific basis for etiologies and treatment strategies.
| Polomano, R C; Mannes, A J; Clark, U S et al. (2001) A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain 94:293-304 |
