Naloxone : actions of an antagonist

Abstract

The opioid antagonist naloxone has a special place in pharmacology __ it has no intrinsic action of its own, but it is able to save lives in the case of life threatening side-effects caused by other drugs. Naloxone is an antagonist for all opioid receptors, but most specifically for the _-opioid receptor, which is the receptor through which opioids such as morphine and fentanyl exert their effects. Those effects include first and foremost analgesia, but also nausea and vomiting, sedation and life-threatening respiratory depression. It is in the case of the latter effect that naloxone can be life-saving, as it is able to reverse respiratory depression. Paradoxically, naloxone, as an antagonist, was a side product of the search for an opioid agonist, one without addictive properties. For many centuries, the addictive properties of opium (and later morphine) were the cause of severe medical and social problems. However, there was (and still is) no alternative to morphine when it comes to analgesia. The solution to this problem was expected to come in the form of a non-addictive opioid agonist and since the start of the twentieth century, scientists have been working to find such a compound. This search has been fruitless with regard to a non-addictive opioid agonist, but has produced several opioid antagonistic drugs. Minor alterations to a drug__s chemical structure can change an agonist into an antagonist. The first opioid antagonist, N-allylnorcodeine was discovered in 1915, by changing a methyl group in the codeine molecule to an allyl group.1 After this discovery, however, the research in non-addictive opioids lay dormant for a while and it would take until 1944 for a second member of the opioid antagonist class, N-allylnormorphine (or nalorphine), to be characterized. Nalorphine showed antagonism for morphine induced respiratory depression,2 but was later found to be a _-opioid receptor agonist as well, with severe dysphoric side-effects (due to its agonism of the opioid receptor).3 Further experimentation with nalorphine__s chemical structure finally yielded N-allylnoroxymorphone, or naloxone, in 1960.4