The existence of an endogenous opioid system had been described as early as 1969. When certain areas of the rat brain were electrically stimulated, analgesia was produced, then reversed rapidly by the opioid antagonist naloxone. In 1975, the first endogenous opioid peptide was identified and named enkephalin. Shortly after, two other opioid peptides, endorphin and dynorphin, were identified. The endogenous opioid peptides are derived from one of three precursor polypeptides and released during stressful times. These precursors undergo complex cleavages and modifications to yield multiple active peptides which act at discrete receptors throughout the body. All of these opioid peptides share a common amino-terminal sequence, called the "opioid motif." The opioid effects of these peptides are quickly terminated by endogenous peptidases.
^-Endorphins are derived from preproopiomelanocortin (Pre-POMC), found in the central nervous system, and act primarily as |x1 opioid receptor agonists. Additionally, Pre-POMC can be cleaved into other nonopioid peptides such as adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), and ^-lipoprotein (P-1-LPH), demonstrating that endogenous opioid peptides are linked to numerous hormones. Preproenkephalin serves as the precursor for met-enkephalin and leu-enkephalin. Dynorphin A, Dynorphin B, and a-neoendorphin and P neoendorphin arise after cleaving preprodynor-phin. The enkephalins act as delta (á)-opioid receptor agonists and are found in areas of the central nervous system, gastrointestinal tract and adrenal medulla. Dynorphins have a bodily distribution similar to enkephalin, but lack their analgesic strength. They act as agonists at kappa (K)-opioid receptors. All endogenous peptides produce their pharmacologic effects through membrane-bound, G-protein-coupled receptors.
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