Molecule of the Month: Opioid Receptors

The world is facing a crisis of pain. On one hand, countless people throughout the world are suffering from chronic pain from cancer and other ailments, but they do not have access to our most effective treatment for pain: morphine and other opioid drugs. On the other hand, the western world is suffering the consequences of widespread availability of opioids. Legally-prescribed opioids give relief to patients with chronic pain, but problems with tolerance and addiction have lead to widespread abuse.

Pain can be a good thing. For instance, the pain we feel when touching a hot stove makes us jerk our hand away, preventing harm. This pain is the result of a complex signaling process: the problem is sensed by receptors in the hand, signals are sent to the brain where they are interpreted as being painful, and finally a signal is sent back to the hand to cause it to jerk away. This process relies on a fine balance between signals that stimulate the message, increasing the level of pain based on the severity of the problem, and signals that inhibit the message, ensuring that we are not overwhelmed. Chronic pain occurs when this balance is not correct, and doctors prescribe opioids to help correct the balance.

Small peptide neurotransmitters, called enkephalins and endorphins, are the natural inhibitors of pain signals. They bind to opioid receptors in pain-signalling cells of the nervous system. Opioids mimic this action, also causing opioid receptors to slow down the pain response. Opioid receptors are typical G-protein coupled receptors (GPCR) that bind to neurotransmitters or opioids on the outside of the cell, and launch a response through G-proteins inside the cell. The structure shown here (PDB entry 4dkl) is one type of opioid receptor bound to an analog of morphine.

As with all neurotransmitters, it is important to stop the signal when it isn’t needed any more. Enkephalins and endorphins are rapidly broken down by peptide-cutting enzymes, stopping their pain-reducing action. Dipeptidyl peptidase III, shown here from PDB entries 3fvy and 5e33, is one example. It breaks down neurotransmitters by chopping off two amino acids from one end.