The molecular perspective: morphine.

The Oncologist 2004;9:717-718 www.TheOncologist.com After a century of effort, morphine remains the most effective weapon in the war against pain. Most painkillers, such as aspirin and acetaminophen, have an upper limit to their painkilling level, but morphine blocks more and more pain with increasing doses. Morphine is far from perfect, however: it causes nausea and constipation, it presents a constant danger of life-threatening respiratory depression, and it is strongly addictive. Chemists have tinkered and modified the basic form of the molecule in a continuing effort to make it more potent and to reduce its severe side effects. Heroin was an early attempt to create an improved version of morphine, but it did not reduce the addictive qualities as hoped. Hundreds of compounds have been tested since then, but none have managed to isolate the desirable painkilling properties from the unwanted side effects. Morphine is so effective because it acts directly at painmodulating receptors in the nervous system, termed opioid receptors. These receptors respond to natural compounds, such as the enkephalin shown in Figure 1, built by our bodies to control the levels of pain experienced at different times. For instance, endorphins may be produced during heavy exercise, reducing pain levels when those levels inhibit strenuous activity. Morphine mimics these natural compounds, binding to the receptors and artificially blocking the pain messages. When morphine binds to opioid receptors, the painkilling message is transmitted inside the cell through a G protein cascade, as shown in Figure 2. The G protein system is the most common method of signaling in our cells. There are thousands of different G protein-coupled receptors, each waiting for a different signal. Each system starts with a receptor that recognizes the signaling molecule, which then activates a G protein inside the cell, which in turn activates an enzyme or an ion channel that spreads the signal throughout the cell. In the case of adrenaline, the G protein activates Fundamentals of Cancer Medicine The Oncologist