Skin pain and muscle pain are categorically distinct from each other. While skin pain is a sharp, spatially localized sensation, muscle pain is a dull, poorly localized and more unpleasant one. We hypothesized that there are specific brain regions preferentially activated by muscle pain compared to skin pain. To test this hypothesis, brain responses were recorded from 13 normal male subjects in response to repeated painful electrical stimulation of the muscle and skin of the left leg, using 3-T magnetic resonance imaging scanner. The common brain regions that responded to painful stimulations of both skin and muscle were the thalamus, anterior cingulate cortex, bilateral insula, contralateral primary and secondary somatosensory cortices, and ipsilateral cerebellum. Brain regions specifically activated by muscle stimulation were the midbrain, bilateral amygdala, caudate, orbitofrontal cortex, hippocampus, parahippocampus and superior temporal pole, most of which are related to emotion. Regions except the midbrain showed contralateral preference. These results suggest that dull sensation, which is characteristic of muscular pain, is related with processing in these brain regions. (C) 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.