The distribution of systemically administered [14C]methadone in the brain of 21-day-old rats was examined by computer-assisted autoradiography. Methadone binding differed 2.5-fold across the more than 90 neural structures examined, with the dentate nucleus having the highest levels and lamina I of the anterior parietal cortex the lowest. Since a full normal probability plot demonstrated that the binding was distributed normally across brain structures (r = 0.99), binding classes were defined in terms of 0.5 standard deviation units from the mean. In addition to marked binding differences between neuronal structures, there were prominent laminar differences in the cerebral cortex, hippocampus, superior colliculus and cerebellar cortex. These highly specific patterns of methadone localization were specifically related to the opioid receptor because naloxone blocked the antinociceptive effects of methadone on the hot-plate test and abolished the distribution of methadone binding in the central nervous system. The relatively high levels of methadone binding in layers III and V of neocortex, sensory relay nuclei, inferior olive, pontine nuclei, cerebellar nuclei and cerebellar molecular layer suggest that the constellation of physiological and neurobehavioral sequelae of perinatal opioid exposure result from specific binding at multiple sites involved in sensory, motor and integrative information processing.
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