The endogenous opioid system is involved in stress responses, in the regulation of the experience of pain, and in the action of analgesic opiate drugs. We examined the function of the opioid system and μ-opioid receptors in the brains of healthy human subjects undergoing sustained pain. Sustained pain induced the regional release of endogenous opioids interacting with μ-opioid receptors in a number of cortical and subcortical brain regions. The activation of the μ-opioid receptor system was associated with reductions in the sensory and affective ratings of the pain experience, with distinct neuroanatomical involvements. These data demonstrate the central role of the μ-opioid receptors and their endogenous ligands in the regulation of sensory and affective components of the pain experience.