Human neuroimaging studies on the physiology of itch have been hampered by the lack of reproducible "on-off" stimuli. Using a previously established biphasic temperature stimulus model, we investigated the cerebral activation pattern of itch processing in 12 healthy volunteers with functional magnetic resonance imaging. Itch was provoked on the right forearm with skin prick application of 1% histamine-dihydrochloride. Local temperature modulation allowed reproducible itch provocation above scratch threshold (defined as 33/100 on a visual analogue scale) during 25 degrees C, whereas itch declined below scratch threshold during the 32 degrees C stimulation period. No itch sensation was reported using 0.9% saline with temperature modulation. Itch sensation above scratch threshold was associated with increased activation of the thalamus, presupplementary motor area, anterior insular, inferior parietal, and dorsolateral prefrontal cortex, and decreased activation of the orbitofrontal, medial frontal, mid-cingulate, and primary motor cortex in comparison to saline. The biphasic temperature model allows rapid modulation of histamine-induced itch. The evoked itch sensation above scratch threshold is processed by a network of brain regions contributing to the encoding of sensory, emotional, attention-dependent, cognitive-evaluative and motivational aspects of itch.