The observation that the narcotic antagonist naloxone could inhibit analgesia produced by electrical stimulation of the brain indicated the involvement of an endogenous chemical in the relief of pain. Multiple endogenous opioid peptides have been identified that have similar pharmacological properties to known narcotic analgesics. The biosynthesis, release, and degradation of opioid peptides have been studied in order to better understand how the manipulation of endogenous opioid systems can be used to produce or augment analgesia. The results of our studies reveal that various conditions and manipulations, such as electrical brain stimulation, acupuncture, stress, and the administration of opioid analgesics, can cause the release of endogenous opioid peptides and possibly endogenous nonpeptide substances. It has also been discovered that nonopioid peptides, such as cholecystokinin, calcitonin, and angiotensin II, can alter the action of opioid analgesics by antagonizing or potentiating their effects. An understanding of the role of endogenous peptides in endogenous opioid mechanisms is necessary for the development of new ways to treat pain and such other disorders as sleep apnea in children (sudden infant death syndrome), head injury, and opioid addiction that involve the activation or alteration of endogenous opioid systems.