This podcast originally appeared on Pythagoras Trousers episode 93 on October 18th 2012
Many scientists spend their lives trying to uncover how things work. But some things are more difficult to understand than others; one of these is the general anaesthetic.
An anaesthetic is a drug that gives you anaesthesia. The definition of anaesthesia is a state in which a patient is, in most cases, rendered insusceptible to pain during surgery. For simple procedures that don’t involve surgery, they are used purely as sedatives. The conventional general anaesthetic is a drug that will put the patient in a state where they have no consciousness, no memory, and certainly no perception of pain.
But how they actually work still remains relatively mysterious. In order to put us in a superficial sleeping state they must somehow interact with the brain. But do they actually mimic our natural sleeping system, or do they interfere with it?
Professor Nick Franks, a professor of biophysics at Imperial College, London, does research on anaesthetics and how they affect our brains.
“We’re interested in what the basic neuronal mechanisms are, and are particularly interested in exploring the possibility that conventional anaesthetic drugs, rather than just depressing the brains activity, which they do, we think its possible that they might do this rather selectively, and it might involve the same neuronal pathways that are involved in natural sleep.
So the idea is that at least, at the low levels of anaesthetics that cause loss of consciousness, sedation, we think it is possible that anaesthetics are recruiting natural sleep pathways. And there is an extremely powerful drive to sleep physiologically. In fact if you don’t sleep you feel very confused, very unwell, and certainly in animals they will eventually die due to lack of sleep, and faster than they would die through lack of food. So sleep is a really powerful drive, so it seems possible, at least, that anaesthetics are recruiting that drive in some way and putting you into an artificial sleep like state.”
Natural sleep is a state in which your brain actively shuts down the pathways that keep us awake. When you’re awake and active, conscious and aware, there are all sorts of neuronal pathways that excite the cortex in your brain. When you go to sleep, these pathways aren’t just shutdown automatically, instead there are other pathways that are activated which inhibit those “awake” pathways. So at some point in your normal circadian cycle, when you are ready to go to sleep, the sleep inducing pathways kick in, switching off the arousal pathways. This happens because the anaesthetics bind to proteins that usually promote natural sleep.
“One thing we have learned over the last few years is that different anaesthetics target different proteins. There are key proteins that are common to many anaesthetics, and there is one particular protein called the GABBA receptor that is a major inhibitory receptor of the brain. It is responsible for making neurones fire less, so it is an inhibitory receptor. So many of these sleep pathways involve the activation of this GABBA receptor to make an inhibitory pathway. And anaesthetics make these inhibitory pathways more inhibitory, so they potentials this GABBA receptor. They make the GABBA receptor more effective.”
When we sleep we go through different stages: we start with a deep, non-dreaming sleep which lasts about 3 hours. After this we go into what is known as REM, or rapid-eye-movement sleep, in which we have our many dreams. In dreaming sleep, your brain is very active – perhaps more active than when you are awake as your brain is alive with mental imagery. But when you are under a general anaesthetic, you’re brain doesn’t look like that at all. Instead, anaesthetics put you into a deep non-dreaming sleep.
So this is the area that Professor Franks and his colleagues are researching. And one of the things he is looking at is the effect of histamines. If you’ve ever taken an anti-histamine you may have noticed that you feel a little drowsy afterwards. It’s because the anti-histamine blocks the production of histamine, an arousal drug, in your hypothalamus.
“We’ve been perusing a theory that those neurons that release histamine were particularly important in the actions of anaesthetics. We modify mice genetically so that pathway will have a different control, and anaesthetics might act differently on that histaminurgic system. So we test in a mouse for example in which there are no inhibitory GABBA receptors on these histamine neurons, and therefore no targets for anaesthetics, to see if the anaesthetics will behave differently. And that is a test to see if this switching off of those neurons is critical to the actions of anaesthetics.”
“We have a contradiction, as often happens. Previous work that we were also involved in seemed To suggest that the turning off of these histaminurgic neurons really did affect anaesthetic sensitivity. However, having modified these mice after a great deal of work, we have found that the inhibitory control of them that was removed, the anaesthetic targets that were effectively removed, and the mice have an identical anaesthetic response. S I think this looks like a fairly definitive disproof of our idea that the histamine system was critical, but, it’s quite possible that other arousal systems are important. But I think we can probably, at least tentatively rule out this particular one.”
Looking at the brains of mice under the influence anaesthetics give Professor Franks a very good indication of how the human brain will react.
“So, the two things we do are you measure a behavioural response to see whether the animal has either lost consciousness. You can’t actually ask a mouse whether it has lost consciousness, so the surrogate that we use is if you put a mouse, or any other animal on its back, and its conscious, it will right itself. And that righting reflex is a very very powerful reflex. And the concentrations of anaesthetics that stop that righting reflex are almost identical to the concentrations that block consciousness in humans. So that’s a very good and close correlation as it is probably a waste of time to ask “is the mouse conscious?” But it’s a very good model. So we measure behaviour. And then we measure electrical signals in their brains, EEG measurements and brain waves. And we know how these look in humans, we know what sort of brain waves we expect for an animal that is conscious and unconscious, as far as we candidate. So those are the measurements we use, we don’t use imaging.”
As it happens, anaesthetics have other, unexpected applications other than putting us to sleep. Anaesthetics, in addition to causing loss of consciousness, can be used protect the brain from injury. This type of anaesthetic is called a neuro-protectant.
“Brain cells that are killed by, lets say a blow to the head, they’re never going to be recovered. But there’s what’s called a penumbra injury surrounding tissue that will die unless its protected. And so the aim of that area is to try and give drugs that will protect against that on-going injury. There are many drugs that have been tried, and many that work in the laboratory. Few, if any, have ever translated into clinical use. Bar some Re anaesthetics that are potentially useful. And there’s one that we have worked extensively on that called the xenon, that’s the inert gas. That is particularly effective as a neuro-protectant. And in any animal models of injury, if the animals breathe xenon, either during or after the injury, even some hours after the injury, we can arrest the development of that injury. And the beauty about something like xenon, and any other gaseous anaesthetic, is that you don’t have to inject it into the blood supply and hope that it crosses the blood-brain barrier. You know anaesthetics will get into the brain, xenon after a few breaths will get into the brain. And in the case of xenon it is not metabolised, it is an inert gas, it’s a simple atom. So, there are no nasty metabolites to worry about. And so we’re looking in a number of animal models whether xenon is a neuro-protectant, which is something we’ve worked on for many years. And indeed there are two trials, a number of trials, going on around the world. one we’re involved in slightly in London where babies who’ve had neonatal asphyxia are being, the standard of treatment at the moment if they potentially suffer brain injury by having a lack of oxygen, their brains are cooled. This trial, in addition to the cooling, adds xenon to the gas they’re breathing. We won’t know for a couple of years, this has been led by colleagues in the Hammersmith, we won’t know for a little while whether that’s going to work. But that’s an application of anaesthetics that we didn’t anticipate.”
Although xenon is an inert gas that wont chemically interact with other things, it will physically interact.
“Everything interacts with everything and xenon is no exception. Xenon will bind to proteins, it’s not a chemical interaction, but it’s a soft interaction. And at sufficient concentrations it will bind by itself to proteins. And we’ve found a couple of proteins which we’ve identified as responsible, probably, for the neuro-protective effects of xenon. And possibly also for the anaesthetic effects of xenon.”
The future of anaesthetic research looks to be an uncertain one. With many functions still to be understood, and new discoveries still to be made, who knows what other benefits anaesthetics could have.