Most of the knowledge about the neurobiological mechanisms of the placebo effect comes from the field of pain and analgesia. Expectation of pain reduction plays a crucial role in placebo analgesia, and this is shown by the reduced effectiveness of painkillers when administered covertly, i.e., unexpectedly. The placebo analgesic effect is mediated by the endogenous opioid systems and antagonized by cholecystokinin in some circumstances. Many brain imaging studies indicate that several areas are involved in placebo analgesia, e.g., those involved in dopaminergic reward mechanisms. The nocebo hyperalgesic effect is mediated by anxiety which activates a cholecystokinin system that, in turn, facilitates pain transmission. The endogenous pain modulatory descending circuits represent the biological substrate for the action of placebos on pain.
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