Imaging of hyperalgesia in rats by functional MRI

Cerebral activation in response to sequences of temperature boosts at the hindpaw was observed in functional magnetic resonance imaging (fMRI) experiments in isoflurane anesthetized rats. Cingulate, retrosplenial, sensory-motor and insular cortex, medial and lateral posterior thalamic nuclei, pretectal area, hypothalamus and periaqueductal gray were the most consistently, often bilaterally activated regions. With the same experimental paradigm, activity changes in the brain following subcutaneous zymosan injection into one hindpaw were detected. These changes developed over time (up to 4h) in parallel with the temporal development of hyperalgesia shown by a modified Hargreaves test, thus reflecting processes of peripheral and central sensitization. When the heat stimuli were applied to the inflamed paw, the hyperalgesia manifested itself as a volume increase of the activated areas and/or an enhanced functional blood oxygenation level dependent (BOLD) signal in all the above-mentioned brain regions. Enhanced BOLD signals were also observed in response to stimulation of the contralateral non-injected paw. They were significant in higher associative regions and more pronounced in output-related than in input-related brain structures. This indicates additional sensitization processes in the brain, which we named cerebral sensitization. Long lasting zymosan-induced hyperalgesia could be monitored with high resolution fMRI in rats under isoflurane anaesthesia. This technique may provide an effective method for testing new analgesics and studying structure specific pain processing.