Severity Of Neuropathic Pain, Sensorimotor Impairments, And Sensory Neuron Abnormalities In Rat Model Of Radiation Induced Neuropathy Is Dose Dependent
Anna E. Riegger, BS, Jagienka H. Timek, BS, Noah Nelson, BS, Amir Dehdashtian, MD, Melissa Daniel, BS, Steven R. Buchman, MD, Stephen W.P. Kemp, PhD.
Michigan Medicine, Ann Arbor, MI, USA.
PURPOSE: Radiation therapy (XRT) is one of the mainstays of cancer treatment, with approximately 50% of cancer patients requiring XRT as part of their treatment regimen. Of these patients, almost 31% subsequently suffer from debilitating neuropathic pain and sensory nerve abnormalities. XRT induced peripheral neuropathy results in progressive, intractable, and often irreversible nerve pain which can have a devastating effect on patientsí quality of life and potentially reduce the overall benefit of the therapy itself. We have previously established a novel rodent model of radiation induced peripheral neuropathy. The purpose of the present study was to assess neuropathic pain, sensorimotor impairments, and sensory neuron abnormalities in both clinically relevant and clinically high dose radiated animals.
METHODS: Eighteen male Lewis rats were randomly assigned to one of three experimental groups: (1) radiation of 35 Gray (Gy) divided into 5 daily doses of 7 Gy/day; (2) radiation of 70 Gray divided into 5 daily doses of 14 Gy/day, and (3) sham-radiated controls. All animals were tested at baseline in both pain and sensorimotor behavioral tests. Pain related measures included mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Sensorimotor testing consisted of evaluation of overground locomotion using walkings tracks with calculation of the Sciatic Functional Index (SFI). Animals were tested serially over an 8 week period. At study endpoint, we performed nerve conduction analysis, electromyography (EMG), muscle force measurements, and all sciatic nerves were taken for histological/histomorphometrical analysis. In a separate cohort of animals, retrograde labeling was conducted in order to assess the level of sensory neuron death following radiation.
RESULTS: All animals that underwent radiation displayed significantly greater hypersensitivity to mechanical stimulation as compared to sham-radiated animals, indicative of chronic neuropathic pain. SFI values indicated sensorimotor impairments in radiated animals, and significantly lower twitch and tetanic muscle forces. Sensory neuron abnormalities and cell death were greater in radiated animals, with the high dose group displaying the most severe decrease.
CONCLUSION: Results from this study demonstrate that neuropathic pain, sensorimotor behavioral impairment, and sensory neuron abnormalities vary as a function of radiation dose administered. Ongoing research is currently assessing novel therapeutic compounds to attenuate debilitating radiation induced sequelae, with the goal of improving the quality of life for cancer patients undergoing XRT.
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