Pleasurable stimuli, including reward, inhibit pain, but the level of the neuraxis at which they do so and the cerebral
processes involved are unknown. Here, we characterized a brain circuitry mediating pain inhibition by reward. Twenty-four
healthy participants underwent functional magnetic resonance imaging while playing a wheel of fortune game with simultaneous thermal pain stimuli and monetary wins or losses. As expected, winning decreased pain perception compared to
losing. Inter-individual differences in pain modulation by monetary wins relative to losses correlated with activation in the
medial orbitofrontal cortex (mOFC). When pain and reward occured simultaneously, mOFCs functional connectivity
changed: the signal time course in the mOFC condition-dependent correlated negatively with the signal time courses in the
rostral anterior insula, anterior-dorsal cingulate cortex and primary somatosensory cortex, which might signify momentto-moment down-regulation of these regions by the mOFC. Monetary wins and losses did not change the magnitude of
pain-related activation, including in regions that code perceived pain intensity when nociceptive input varies and/or receive
direct nociceptive input. Pain inhibition by reward appears to involve brain regions not typically involved in nociceptive intensity coding but likely mediate changes in the significance and/or value of pain
