Visualizing acute pain–morphine interaction in descending monoamine nuclei with Fos

The effect of morphine is often studied in the absence of pain, and it remains poorly understood if and how noxious stimulation may change the activity state of descending pain-modulatory pathways and their response to morphine. Immunohistochemical double-labeling technique with Fos and markers for noradrenergic and serotonergic neurons was used to examine if an intraplantar formalin injection (an acute noxious input) changed the effect of morphine on noradrenergic neurons of the A7 and A5 cell groups, and serotonergic neurons of the nucleus raphe magnus (NRM). Four groups of rats were analyzed: (1) control injected with normal saline subcutaneously, (2) rats treated with FORMALIN into the hind paw 30 min after subcutaneous normal saline injection, (3) rats injected with MORPHINE sulfate subcutaneously, and (4) rats treated with formalin into the hind paw 30 min after subcutaneous morphine injection (morphine/formalin). The average number of total Fos-labeled cells per section was unchanged in all areas of analysis in all treatment groups. However, the percentage of noradrenergic neurons in the A7 and A5 cell groups that contained Fos was significantly increased in the morphine/formalin group compared to all other groups, while no differences were found in serotonin cells in the NRM. In contrast with the view that morphine simply blocks access of nociceptive information to supraspinal brain areas, these data suggest that noxious stimulation has the capacity to modify the actions of morphine on brainstem noradrenergic nuclei, which may participate in descending pain modulation as well as other behavioral responses to pain.