Forging links between the scientific community and the devolved nations

by Henry Lovett, Policy & Public Affairs Officer

Politics does not only happen in Westminster. The United Kingdom of Great Britain and Northern Ireland has a complex system of internal devolution, with Parliaments or Assemblies in Belfast, Cardiff and Edinburgh, as well as London. The Physiological Society is always keen to engage with the devolved administrations to discuss local industries and university research specialities, as well as the impact of their unique local political situation on UK-wide concerns such as the Industrial Strategy. Our policy team has just come back from Edinburgh, where Science and the Parliament 2017 was taking place in the city’s impressive science centre, Dynamic Earth.

devolved1

Talks being given at the Welsh Assembly for “Science and the Assembly”

The theme of Science and the Parliament was “Science, Innovation and the Economy”, but of course this was broadened in everyone’s mind to include Brexit. The UK government has claimed that science, technology, and innovation will be at the heart of our post-Brexit economy, and the discussion centred on what this means for Scotland (an area that voted to remain in the EU, which was also a big issue in the Scottish Independence referendum). Despite being a hotbed of commercialisation of university-derived research, there was much discussion about how to improve the progress of start-up companies in Scotland. They take longer to reach a turnover of £1m than anywhere else in the UK or most of Europe. It was felt that the new structures around research and innovation funding, UK Research and Innovation, need to include significant representation from Scotland (and the other devolved nations) not to become too England-centric. There was also general concern that fundamentals such as infrastructure and connectivity affect start-up companies, so investment has to be made to make areas of Scotland attractive places to base a company.

devolved2

Physiological Society Members who visited our stand at “Science and the Parliament” in Edinburgh

Earlier in the year we also attended Science and the Assembly in Cardiff, and Science and Stormont in Belfast. Each of these events has a slightly different take on how to explore science in the local area. Cardiff focused on antimicrobial research, while Belfast titled their event “Skills for Science and Innovation”. The research discussed in Cardiff was very impressive, both from local universities and companies based in the area. The talks in Belfast had a much more political focus, with concerns being raised about the effects of the ongoing suspension of the Northern Irish Assembly. This was halting new initiatives, including those designed to address the serious problem of the supply of science teachers in Northern Ireland.

devolved3

Society Members who visited our stand at “Science and Stormont” in Belfast

At each of these events we were delighted to have an exhibition stand to raise the profile of physiology and increase recognition of the policy work we are undertaking. These events present great opportunities to mingle with people involved locally in scientific research and outreach, in order to discuss everyone’s projects and initiatives. We were pleased to also welcome Physiological Society members based locally to discuss our policy work with them, find out their views and concerns for The Society to address, and generally catch up about the exciting physiology research being done across the UK.

Thanks are due to all the Members who visited us, all the politicians who attended and spoke at the events, and the Royal Society of Chemistry for arranging these valuable opportunities to connect with politicians and scientists across the UK.

Night at the Vet College

Step inside the Royal Veterinary College’s inspiring campus on 22nd November for an evening of animal excitement at ‘Night at the Vet College’, in collaboration with The Physiological Society.

The theme of the night is ‘Wellbeing’, based on The Physiological Society’s 2017 theme of ‘Making Sense of Stress’. Complete with canine scientists, TV stars and a dissection, this event is not to be missed!

Wellbeing 2017 image crop

Go behind the scenes at the RVC’s 226 year old Camden campus, admiring animal skeletons and specimens which have shaped the study of thousands of veterinary students. In the main Anatomy Museum you have the chance to get up close and personal with your favourite specimen for a drawing session, with artist Tim Pond.  Tim has drawn every animal under the sun, and will be showcasing his animal anatomy studies, which are fundamental for understanding animal wellbeing.

At 6 pm, move into the Great Hall for an exciting talk by the star of ‘Trust Me I’m A Vet’, Judy Puddifoot, who will be discussing the work behind the scenes of the programme, in particular her work with dogs, guinea pigs and tortoises!

Judy_Puddyfoot

Judy Puddifoot on Trust Me I’m a Vet. ©BBC Two

Throughout the college you will find stands dedicated to different professions who care for animal wellbeing, including staff from our Hertfordshire Queen Mother Animal hospital talking about how your dog could save lives by giving blood. Check out visiting animal charities and community teams to see how their work with animals benefits both human and animal wellbeing. For instance, hear about how dogs are trained to become assistance animals, from The Dogs for Good team. Try on surgical gowns and develop your clinical skills in our mock clinic area; our neighbours the Beaumont Sainsbury Animal Hospital will be showcasing their accredited dog and cat waiting rooms, complete with research-approved classical music for the cats!

At 7 pm, get ready for a dissection conducted by the Head of Anatomy services, Andrew Crook MBE. He can assure you that “this will be a fantastic opportunity to witness a real dissection and learn about anatomical structures first hand.” You can either watch the dissection first hand (max 100 spaces in the theatre, first come first served), or if you prefer, the whole thing will be being live streamed to the Great Hall lecture theatre, for you to watch the process without the olfactory component.

Dissection

©Royal Vet College

By taking part in our activities you can learn about the world–class science being produced by our researchers, including ferret preferences and how fractures relate to neurobiology. Postdoctoral Researcher Dr Rowena Packer and her team will be talking about stress levels in Border Collie dogs, how it is affected by neurological disorders, and how they can measure it. You will find out how this cutting-edge research will benefit the wellbeing of dogs with epilepsy!

Manager of the Grant Museum of Zoology and author Jack Ashby is also joining us with his new book – Animal Kingdom: A Natural History in 100 Objects.

You’ll have to try and remember all you heard about throughout the evening, because our student bar will be hosting a Pub Quiz. Time to use your new animal knowledge to win prizes!


Night at the Vet College is on November 22nd, 5.30-10pm, at the Royal Veterinary College’s Camden Campus: 4 Royal College Street, NW1 0TU (10 mins walk from Kings Cross, Mornington Crescent or Camden Town tube stations). You can book your free place here, however there is limited capacity so early booking is encouraged: https://www.eventbrite.co.uk/e/night-at-the-vet-college-wellbeing-tickets-38770001117

Stress and the gut – it’s not all in your mind (Part 2)

By Kim E. Barrett, Division of Gastroenterology, Department of Medicine, University of California, San Diego, USA, @Jphysiol_eic.

This article originally appeared in our magazine, Physiology News.

The numerous microbes living inside of us help break down nutrients and “educate” our immune system to fight infection, but how do they help us respond to stress?

The microbiota as a mediator of responses to stress

Gut microbes change when people have intestinal diseases, such as inflammatory bowel diseases and irritable bowel syndrome. Indeed, some of the characteristics of these diseases can be transferred to animals in the lab that lack microbes, using microbes from diseased mice or humans. It is also becoming increasingly clear that gut microbes and their products may have effects well beyond the confines of the intestine itself.

Perhaps the most intriguing aspects of this area of research is that which ties the composition of the gut microbiome to brain function and the brain’s response to stress. Further, the adverse effects of stressful situations on gut function depend on the presence of intestinal microbes. To date, research supports bi-directional communication between the gut and brain (pictured below) that influences the normal function of both bowel and brain alike. This may explain, for example, why some digestive and psychiatric disorders go hand-in-hand (Gareau, 2016).

gut brain

Bi-directional communication between the gut and brain.

Evidence in human patients largely shows correlation not causation so far. Still, it is intriguing to observe that derangements in the microbiome have been associated with many conditions, including depression, autism, schizophrenia and perhaps even Parkinson’s disease (Dinan & Cryan, 2017).

Therapeutic manipulation of the microbiota – from probiotics to transplants

So if both intestinal and neuropsychiatric conditions are potentially caused by changes in the gut microbes (at least in part), and if such alterations also mediate the impact of stress on the relevant organ systems, can we mitigate these outcomes by targeting the microbiota?

Several approaches have been posited to have either positive or negative effects on the make-up of the gut microbiota and its intestinal and extra-intestinal influences.  Perhaps the most obvious of these is the diet. While the gut microbiota was at one time felt to be relatively immutable in adulthood, improved  techniques indicate that its make-up, in fact, is profoundly influenced by the composition of the diet and even by the timing of meals. For example, Western diets, high in meat and fat, decrease the diversity of the microbiota (and may even promote the emergence of pathogenic properties in commensals), whereas diets rich in plant-based fibre increase it.

healthy_diet.jpg

Another approach to targeting the microbiota is the use of antibiotics, although for the reasons discussed in Part 1, these are likely to be mainly deleterious, particularly early in life. The composition of the microbiota can also be altered directly by the administration of probiotics, which are commensal microorganisms (the host benefits, while the microbes are unaffected) selected for their apparent health benefits that can be taken orally.  Studies in animal models demonstrate that probiotics can improve both gut and cognitive function in animals exposed to a variety of stressors, or can negate the cognitive dysfunction accompanying intestinal inflammation or infection.  However, not all probiotics are created equal, and much work remains to be done both to validate animal studies in human clinical trials, and to define characteristics of probiotic strains that predict efficacy in a given clinical setting.

Perhaps the approach to targeting the microbiota that has attracted the most recent public attention is the practice known as faecal microbial transplant (FMT), where faecal material is transferred from a healthy donor (often a relative) to someone suffering from a specific intestinal or extraintestinal disease.  Enthusiasm for FMT derived initially from its dramatic efficacy in some patients suffering from disabling and persistent diarrheal disease as well as other symptoms associated with treatment-resistant infections by C. diff (a harmful bacteria).  More recently, there have been encouraging data suggesting that FMT may be effective in producing remission in inflammatory bowel disease, although the long-term consequences are unknown, and larger, well-controlled studies are needed.  Exploratory reports even suggest beneficial effects of FMT on gastrointestinal and behavioural symptoms of autism, or in obesity and metabolic syndrome (a cluster of conditions that occur together and increase your risk of heart disease, stroke and other conditions), but much further work is needed to validate these preliminary data.  Ideally, FMT procedures should be conducted under carefully-controlled and physician-supervised conditions to screen for the potential presence of pathogens or toxins.  Nevertheless, despite the obvious “yuck” factor, “do-it-yourself” instructions can readily be found online (there are even Facebook groups), and some individuals are sufficiently distressed by their condition to give it a try.

faecal_transplant_pill

Yep, this is exactly what you think it is.

Mitigating negative effects of stress

In conclusion, it is clear that our response to stress, whether manifested in our thought patterns or in our gut, is dramatically shaped by the microbiota that resides in the intestines.  Particularly in humans, studies conducted to date have largely been confined to cataloguing the key players in a given setting, but animal data are provocative, and studies focusing on microbes’ roles and functions in humans will doubtless follow.   No matter what, in the coming years, the explosive growth of studies aiming to target the microbiota for health benefits should give us a much better understanding of which approach, if any, is likely to be most beneficial for a given condition and even a given individual, since host factors clearly can also impact our microbial composition.  This work holds the promise of ameliorating negative effects of stress, and perhaps may offer new avenues for the therapy or even prevention of the myriad of stress-related disease states that are increasing in incidence in developed countries.


References

Dinan TG & Cryan JF. (2017). Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration. The Journal of physiology 595, 489-503.

Gareau MG. (2016). Cognitive function and the microbiome. International Review of Neurobiology 131, 227-246.

 

Stress and the gut – it’s not all in your mind (Part 1)

By Kim E. Barrett, Division of Gastroenterology, Department of Medicine, University of California, San Diego, USA, @Jphysiol_eic.

This article originally appeared in our magazine, Physiology News.

We all know that stress has an impact on the function of our digestive system. Whether it is the transient butterflies that accompany an exam or an interview, or the more toxic consequences of chronic stress, our experience of our world and its challenges can profoundly alter our digestion, absorption of nutrients, and excretion.

What has been less fully appreciated, until recently, is that communication between the brain and gut is bi-directional. Gut illnesses may be accompanied by brain disorders, such as anxiety, depression, and memory problems.  The brain and spinal cord are in constant communication with the gut, in part via the “little brain” – the nerves present in the gut that communicate with the brain.

While we humans like to think that we are masters of our own universe, in fact we, along with all other beings, are superorganisms. Our bodies consist not only of our own cells and genome, but also of distinctive populations of ‘friendly microbes’, along with their genes and ability to break down compounds. This so-called “microbiome” is made up mostly of bacteria, the best-studied populations, but also other microbes such as fungi and viruses (which are only now beginning to be examined).  Specialized groups of microbes inhabit various parts of our body, such as the intestines, mouth, skin, lungs, and genitals. The most extensively characterized of these microbiomes is the collection of bacteria in the gut, consisting of thousands of species in a typical healthy human adult. They reside throughout the intestines, but are most heavily concentrated in the colon. There are as many as 1014 of them throughout the gut. That’s ten times the number of human cells in the entire body (Sekirov et al., 2010). Recently, the 10:1 ratio has been disputed, with a claim that the numbers of human cells and gut bacteria are of the same order of magnitude (Sender et al., 2016). Even if this true, the microbes collectively have more genes than our cells do.

We are rapidly learning the ways in which these gut microbes may be important mediators of the cross-talk between the gut and brain. They are, in turn, influenced by environmental conditions, such as stress and diet, in ways that change their impact on both our thinking and digestion.

gut brain

 

Friendly microbes – what do they do for us?

Microbes, in the gut or elsewhere, are not essential for life, as illustrated by the ability to raise animals in a sterile environment in the lab. Nevertheless, the gut microbes in particular offer several advantages to the organism they inhabit. For us, they break down nutrients we can’t, such as dietary fibre, drugs, carcinogens, and compounds that break down into vitamins.  Similarly, the microbiota “educate” the immune system of organs such as our lungs and intestines to fight foreign substances but tolerate the proteins of broken-down food or other harmless microbes.

The organisms of the microbiome also defend against pathogens by crowding them out, producing substances that kill bacteria or keep them from reproducing, or causing the host to create those lethal compounds itself. For this reason, antibiotics that kill beneficial microbes can render patients susceptible to intestinal infections and overgrowth of harmful bacteria, such as Clostridium difficile (C. diff).

gut brain 2

3D cellular model of an intestine by Ben Mellows, PhD Student, University of Reading, UK

Gut microbes and birth

We think that gut microbes exist in the body immediately after birth, although some controversial data suggests the presence of microbes in the fetus before birth. Animals without microbes can be born via Caesarean section (C-section), implying that even if there are microbes in the womb, organisms don’t need them to survive (Perez-Munoz et al., 2017).

For babies delivered vaginally, their gut microbes are initially very similar to the mother’s vaginal microbiota, whereas they differ substantially for babies delivered by C-section. An intriguing recent study partially restored “normal” microbes in the gut, mouth, and skin by exposing babies delivered via C-section to the mother’s vaginal fluids. The authors thought that this might reverse the known association between C-section deliveries and an increased risk for immune and metabolic disorders (Dominguez-Bello et al., 2016).

For the first year or two of life, the baby’s microbes are relatively simple and variable, but they gradually take on the characteristics of a mature, adult-like microbiome. These early years are also a critical period for maturation of the immune system, so it makes sense that disrupting the maturation of the infant’s microbes also predisposes them to autoimmune and allergic diseases. For example, the increasing tendency to protect babies from germs or an excessive early-life use of antibiotics may set them up for an increased later risk of asthma, metabolic disease or obesity. This is called the “hygiene hypothesis” (Schulfer & Blaser, 2015).

Stay tuned for the part 2 of the series next week to learn about how gut microbes respond to stress, and the efficacy of therapeutics, from probiotics to transplants.


References

Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, Bokulich NA, Song SJ, Hoashi M, Rivera-Vinas JI, Mendez K, Knight R & Clemente JC. (2016). Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med 22, 250-253.

Perez-Munoz ME, Arrieta MC, Ramer-Tait AE & Walter J. (2017). A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome 5, 48.

Schulfer A & Blaser MJ. (2015). Risks of antibiotic exposures early in life on the developing microbiome. PLoS Pathog 11, e1004903.

Sekirov I, Russell SL, Antunes LC & Finlay BB. (2010). Gut microbiota in health and disease. Physiological reviews 90, 859-904.

Guardians of the brain under pressure

By Sevda Boyanova, @boyanova_sand Hao Wang, @olivia_hao, King’s College London, UK

In England, more than 1 in 4 adults are affected by high blood pressure, making it the third most common cause of premature death, after smoking and poor diet. Globally, 1.5 billion people are expected to have high blood pressure by 2025. This ‘silent killer’ usually occurs without symptoms, and contributes to more than half of heart attacks and strokes.

hypertension

Recently, scientists have revealed a connection between high blood pressure and the disruption of the gateway to the brain’s blood circulation, called the blood-brain barrier. These disruptions might lead to problems in the part of our nervous system involved in heart rate and blood pressure regulation (called the autonomic nervous system), thus contributing to high blood pressure.

So, how exactly does the blood-brain barrier work? The blood-brain barrier is the boundary between the blood flow that is circulating around our body, and the brain. Its function is two-fold: it regulates the balance of molecules flowing in and out of the brain, and also protects the brain from toxic substances. It’s formed by the cells that make up the walls of capillaries, tiny blood vessels in the brain. These cells, called endothelial cells, are joined together tightly so that blood contents cannot cross into the brain like they do in other parts of the body. The cells of the brain capillaries also contain transporters which move specific molecules across the walls of the capillaries. Surrounding the capillaries are three types of cells – astrocytes, pericytes and microglia – which work together with them to maintain a stable blood composition, allowing the brain to function properly. Scientists have implicated three players in the link between the blood-brain barrier and high blood pressure.

Blood Brain Barrier

This cake, submitted to our #BioBakes competition, represents the blood-brain barrier, with the cells of the blood vessel wall (blue) tightly joined by adhesive molecules (green squares) so that potentially harmful components in the blood cannot cross.

The first is a molecule involved in increasing blood pressure by constricting blood vessels (called angiotensin II). Angiotensin II can make the blood-brain barrier more porous which may affect the nervous system’s control of blood pressure. However, at the moment it is not clear if blood-brain barrier disruptions happen prior to or as a result of high blood pressure.

The second is molecules involved in the immune response. High blood pressure is related to low levels of inflammation (the first response when a threat to the body is detected), which is enough to activate the immune system. This activation leads to more inflammatory cells and molecules in the blood. These molecules can affect the structure of the blood-brain barrier, weakening it. Researchers have shown an increase in molecules that take part in the inflammatory response and in the production of white blood cells, during high blood pressure and heart failure. Therefore, these factors may play a part in the initial dysfunction in the blood-brain barrier, and may work alongside angiotensin II to worsen the disease.

The final player comes from the brain itself, in the form of cells that mediate inflammation. These are some of the brain cells that aren’t neurons, called astrocytes and microglia. These cells are normally involved in maintenance, surveillance and repair of the brain. However, researchers have found that microglia might be responsible for sustaining high blood pressure and astrocytes might work together with the microglia to release inflammatory molecules in response to infection by bacteria or viruses. Therefore, glial cells might have an effect on the blood-brain barrier’s ability to keep harmful molecules out. Also, there is evidence that glia could influence the activity of the autonomic nervous system (involved in heart rate and blood pressure regulation); in animal models, increased glial activation happens in brain regions important for the control of blood pressure.

The growing area of research on the link between the blood-brain barrier and high blood pressure is exciting because the blood-brain barrier is a very important target for new therapeutics. Further investigation of the mechanisms involved in maintaining the integrity of the blood-brain barrier will be useful for developing interventions targeted at treating or limiting the progression of conditions such as high blood pressure.


Reference:

Setiadi, A. et al., 2017. The role of the blood-brain barrier in hypertension. Experimental Physiology.

How loud is loud: the physiology of ear ringing

by Thomas Tagoe, Accra College of Medicine, @Tom_DAT

Benedicta took in the sweet smell of flowers in the field as she felt the chill of a cool breeze blowing over her. She could hear the sound of rushing waters from the stream nearby as she lay in the grass biting into a freshly baked doughnut and marvelling at the birds flying high over-head.

In the space of a few seconds, Benedicta had all her five main senses stimulated, providing her with information about the world outside her body. Each of these senses is specialised to a specific part of the body; nose to smell and skin to touch, eyes to sight, ears to hearing, and tongue to taste. Although each of these senses is assigned to a specialised part of the body, it is all interpreted by one part of the body: the brain.

Brain

The five organs respond to different stimuli and convert it all into one type of signal, electricity, which the brain can understand. Light, sound, touch, and odours are all converted to electrical signals which the brain interprets to let us see beauty, hear melodies, and experience the world. This is part of why the brain uses 25% of the body’s energy although it makes up only 2% of the body weight.

Of all the organs and systems which convert a given sense to electrical signals, the auditory system is one of the most impressive. It converts vibrations in the air, better known as sound, into an electrical signal for the brain. Like any finely tuned machine, the auditory system can start to fall apart if abused, such as through exposure to prolonged periods of loud sound. To understand how this can happen, it is best to appreciate how the system works under normal conditions.

Anatomy_of_the_Human_Ear_en

The outer part of the ear, known as the pinna, funnels sound in the air towards the ear canal. This is the reason cupping your hands behind your ears makes hearing better. Once the sound is channelled into the ear canal, it vibrates the ear drum which is connected to three small bones known as the malleus, incus and stapes. These three continue the chain of vibrations which ends in the cochlea, a spiral-looking organ where specialised hair cells are attached to a surface which is tuned like a guitar string. Different frequencies of sound cause vibrations in various sections to bend these hair cells; high frequency sounds like that of a whistle vibrate the bottom end while low frequency sounds like a bass drum vibrate the top end.

These hair cells are the pivotal point in the whole auditory system. Each one that bends from vibrations sends a unique electrical signal. The louder the sound, the more they bend, sending a stronger electrical signal to the brain. Once the electrical signal is in the brain, various bits of information are teased out of it to help us identify language, music, tones and much more.

Ear hair cells

So how can the whole system go wrong? Imagine the difference between beating a drum with open palms and pounding on it with clenched fists; that’s the difference between the effects of normal and loud sound. Loud sounds cause strong vibrations which can eventually destroy the hair cells. This primarily leads to hearing loss but can also lead to tinnitus, the perception of sound in the absence of an external stimulus, typically experienced as a “ringing in the ears”.

Tinnitus is an interesting condition because it suggests that somewhere in the brain, a false signal is being generated in response to a sound which does not exist in the outside world. There are a number of researchers working to understand how this occurs. Their findings suggest that after exposure to loud sound, some of the cells in the brain area called the dorsal cochlear nucleus become easily stimulated, making them respond inappropriately to signals. This and other findings could be traced back to the hair cells in the cochlea, suggesting that once these hair cells get damaged, irrevocable changes follow in the brain.

How loud is loud

The dangers posed by prolonged exposure to loud sound have been known for a while now. So much so that many countries require by law that people who work under conditions of loud sound wear ear protection. Now isn’t it quite curious that as one group of people are required by law to wear ear protectors, while another group willingly expose themselves to the same dangerous levels of sound. Think of the last time you were at a concert, on a night out, or better yet, turned up the volume in your head phones while travelling home.  The short or long-term damage caused by prolonged exposure to loud sound, whether from headphones or planes remains the same: hearing loss and tinnitus.

How do pain meds lose their effect?

By Julia Turan, Communications Manager

You know something’s not right when more Americans are dying from pain medications than illegal drugs. This opioid crisis is filling headlines, and rightly so. However, for patients with chronic pain, tolerance to opioids such as morphine, not addiction, is the real issue. Tolerance is not usually a problem for acute pain after injuries or surgery, but for chronic pain, the patients need the drug to work over a long period.

Most studies have focused on how tolerance affects individual brains cells (neurons). New research from The Journal of Physiology clarifies a piece of the puzzle of how opioid tolerance changes the communication between neurons. This brings us one small step closer to one day developing pain therapies that avoid the development of opioid tolerance.

shutterstock_34328518.jpg

Tolerance to a drug means that larger and larger amounts are required to achieve the desired effect. Patients can become tolerant regardless of whether or not they are addicted. Tolerance does not result from abusing the drug, but rather, it can occur even when the patients follow their course of treatment as required.

The research, led by Adrianne Wilson-Poe and Chris Vaughan at The University of Sydney looked at rat brain slices after giving the animals a low dose treatment of morphine that produces tolerance. To study this, the researchers used a technique that records electrical activity in an area called the midbrain that plays an important role in the pain-relieving effects of opioids. Rather than examine individual neurons they measured how neurons talk to each because this communication is how the brain works.

BrainDiagram

To understand their findings, we need to understand a bit about how our neurons talk to each other. To send a signal, molecules travel from the sender brain cell to the receiver across a gap called the synapse. The synapse has two sides, the pre-synapse and the post-synapse. The pre-synapse is part of the brain cell sending the message, and the post-synapse is part of the receiving cell.

One of the molecules sent between neurons is called GABA. Opioids normally decrease the release of GABA. After chronic treatment with opioids, the researchers found that their dampened effect was due to fewer molecules of GABA being available on the sending side. Consequently, opioids had less of an effect on GABA release from the sending side, as there were fewer molecules around. This reduced communication between neurons is likely to contribute to reduced effectiveness of opioids after chronic treatment.