DYSPHORIA. It sounds rather lovely to me, summoning up a flower bedecked Greek goddess or perhaps a Tennyson heroine, waving off her noble but ill-fated knight. Actually, it is the evil twin of euphoria, and means a state of dissatisfaction and indifference to life. Both of these conditions, however, among several other psychological and physical states, are mediated through opioid receptors, which have been the subject of some recent groundbreaking studies.
Opioid receptors (OR) are found in the cell walls of the central nervous system, that being the brain and the spinal column, as well as the peripheral nervous system, which relays messages from limbs and organs. They receive signals from endorphins, the feel good neurotransmitters produced by exercise, love, spicy food and orgasm, endomorphins, the body's naturally produced painkillers, and nociceptin, which regulates the flow of dopamine, the brain’s reward system. They have also been used and abused since time immemorial because of their reaction to opioid drugs.
The strongest and most widely used medicinal painkillers and sedatives, including morphine and codeine, are derivatives of opium. These drugs are extremely effective but are accompanied by a raft of unpleasant side effects such as constipation, breathing difficulties and of course dependency, which can lead to withdrawal syndrome. The drugs also produce a strong sense of euphoria, which has resulted in the pervasive misuse of medicinal drugs as well as the devastation wreaked across the globe by another opium derivative, heroin.
The hope is that by studying the structure of the opioid receptors, which are the targets of these drugs, it may be possible to design drugs that can administer the pain relief without the undesirable side effects. To study the structure though, the proteins must be crystallized and subject to X-ray analysis in a process known as X-ray crystallography. Until recently, this was thought to be impossible, mainly because these structures contain flexible loops that do not co-operate into crystal lattices but also because they are located in the lipid-based cell walls and as such are particularly difficult both to isolate and to crystallize.
Technological breakthrough came in 2007 as a molecule was found to anchor the errant loop and a method of crystallising the proteins in a lipid-based medium was developed. Raymond Stevens at the Scripps Research Institute in La Jolla, California and Brian Kobilka at Stanford University, California pioneered these methods, and between them this year they have successfully isolated and solved the structures of all four different types of opioid receptors.
Stevens’ lab produced structures for a Kappa-OR, which is a key receptor for dysphoria, pain reduction and sedation, and a nociceptin receptor, which regulates emotional and instinctive reactions through the dopamine pathway. The Kobilka lab solved the structure of a Mu-OR, which mediates pain killing, euphoria and dependence among other things, and a Delta-OR(4), which is less well understood, although known to be active in pain management. They discovered that the opioid receptor binding pockets contain two distinct regions: an upper ‘address’ region that recognizes and selects the correct opioid and a lower ‘message’ region that is believed to interpret the specific chemical signal.
Clearly this knowledge is invaluable in the search for safer painkillers, although much work remains to be done. The proteins have been necessarily inactivated and immobilised for crystallisation, which, whilst a great leap forward, does not reflect the contortions of the receptors in their natural state. The next stage involves experiments and simulations to recreate this flexibility so that an appropriately dynamic partner can be devised.
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