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The discovery of an endogenous opioid system has been rapidly followed by animal studies suggesting its importance in neuroendocrine regulation and behavior. Abnormalities of these functions in affective illness suggest that evaluation of behavioral and hormonal responses following the clinical administration of opiate agonists or antagonists might yield information pertinent to the pathogenesis, diagnosis, and treatment of depression. However, initial double-blind controlled clinical studies have yielded little evidence to support this suggested involvement of the opioid system in affective illness. Acute administration of opiate agonists has sometimes yielded a mild antidepressant response in depression, and naloxone has occasionally been reported beneficial in mania. There is, however, little to suggest that these responses are specific to affective illness. A decreased prolactin response to morphine administration has been reported in depression, but is not direct evidence of opioid system dysfunction in depression since abnormal prolactin responses to other challenges in depression have previously been reported. The endogenous opioid system is actually multiple systems marked by distinct distributions of multiple endogenous opioid peptides and opiate receptor subtypes, as well as varying accessibility to drug administration. Future challenges in depression may rely upon the development of opiate agonists and antagonists with preferential binding to opiate receptor subtypes and preferential distributions to stress particular endogenous opioid systems. Opiate peptide challenges may well be administered intrathecally to overcome the blood-brain barrier. Opiate antagonist challenges will rely upon increasing doses of naloxone, up to 10 mg/kg, in order to increase the range of blocked endogenous opiate systems. Chronic administration of challenges has been a seldom used strategy but may be important in evaluation of the physiology of sensitization and tolerance to pleasure in affective illness.