Molecular mechanisms of opioid receptor signal transduction.

The analgesic and antidiarrhoeal uses of opium were known to the Sumerians and predynastic Egyptians. During 5000 years of medicinal use, opium has become associated with countries, cultures and prominent individuals, and through several modifications, remains an extensively used analgesic and addictive drug. Morphine, the principle active compound in opium, was first isolated by the German chemist Friedrich Sertuner in 1805. Replacing opium in therapy, its high potential for abuse was quickly discovered. Attempts to develop safer morphine analogues have spawned many compounds including heroin, a compound initially hailed as a safer and less addictive option. To date, however, no compound has proven free from a liability to be abused. Nevertheless, the search for safer morphine analogue led to the synthesis of the first antagonist, naloxone, and several other non-endogenous agonists and antagonists, effectively creating the first tools for opioid research. While pharmacological characterization is crucial, the search for safer analgesics requires a thorough understanding of the mechanisms of cellular loss of responsiveness. The recent cloning of opioid receptors has created a new wave of research in the development of opioid tolerance, which may lead to a better understanding of this phenomenon.