Opiates derived from the opium poppy, Papaver somniferum, have been used for millenia for their anti-diarrheal, analgesic and euphoric properties. More recently, endogenous peptides, enkephalins, dynorphins, and endorphins, were found to bind to the same sites as opiate alkaloids. The receptors for the classical opioids are three related GPCRs, mu, kappa, and delta, that activate Gi/o to reduce intracellular cAMP levels. Most clinically used opioids function by activation of the mu opioid receptor. Activation of the kappa opioid receptor by selective agonists also produces analgesia, primarily mediated by spinal sites, but causes dysphoria and psychosis instead of euphoria. The kappa receptor at central and peripheral sites is also largely responsible for the anti-diarrheal effects of opiates.