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Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used 15O-water and positron emission tomography to investigate dose-dependent effects of the short-acting μ-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers.Positron emission tomography measurements were performed with injection of 7 mCi 15O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 μg · kg−1 · min−1 remifentanil, and 0.15 μg · kg−1 · min−1 remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach.During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray.Remifentanil induced regional cerebral blood flow increases in the cingulofrontal cortex and periaqueductal gray during pain stimulation, indicating that μ-opioidergic activation modulates activity in pain inhibitory circuitries. This provides direct evidence that opioidergic analgesia is mediated by activation of established descending antinociceptive pathways.