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Neurons in the medullary raphe magnus (RM) are important in nociceptive modulation. The responses of RM cells to noxious heat and to analgesic doses of opioids have led to the hypothesis that OFF cells inhibit and ON cells facilitate nociceptive transmission in the anesthetized animal. However, little is known of how RM contributes to nociceptive modulation in behaving animals. The proposed experiments focus on the physiology of non-serotonergic RM cells in unanesthetized, freely behaving rats. The experiments proposed in Aim 1 compare the neuronal responses to noxious heat and to systemic morphine in anesthetized and unanesthetized conditions. The remaining aims will further our understanding of how RM cells are activated in behaving rats. Recent experiments suggest that non-serotonergic RM cells have state-dependent discharge in a pattern that is correlated to their response to noxious heat. However, since only a small number of neurons were studied and since the protocol was not completed for many cells, our preliminary findings need to be confirmed and extended. Therefore, RM cells, characterized by their response to noxious heat, will be recorded in freely behaving, unrestrained rats as they cycle through waking, slow wave sleep and paradoxical sleep states. Unit discharge pattern and rate during sleep and wake states will be compared. Neuronal and behavioral responses, including motor and cardiovascular components, to thermal stimulation of either warm or noxious intensity, will be compared for stimuli applied during different behavioral states. Similarly, the responses of RM cells to innocuous mechanical and auditory stimulation will be tested and compared for stimuli applied during waking, slow wave sleep or paradoxical sleep states. Since sensory modulation commonly accompanies active movements, RM cell and motor responses to noxious thermal stimulation will be systematically studied during drinking, eating and grooming. The final aim will test whether RM cells contribute to the decrease in sleep time observed during chronic pain conditions. First, RM cell discharge will be continuously recorded during the development of arthritis and will be compared to the development of arthritic hyperalgesia and to the sleep/wake pattern exhibited by the animal. Second, microinjection of the GABAA receptor antagonist, bicuculline, which is known to activate RM OFF cells will be used to test whether OFF cell activation can increase sleep time in arthritic animals. To determine whether OFF cells act primarily on sleep/wake regulation or nociceptive transmission, the effects of bicuculline on sleep/wake pattern and spontaneous pain behaviors will be compared.

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