Posts Tagged ‘ biochemistry ’

Neuroscience Friends!

I’ve just returned from a thrilling weekend at the BIL Conference in Long Beach, California (yes, the pun on “TED” is very intentional) where I met all kinds of smart, fun people – including lots of folks who share my love for braaaiiins!

The conference was held in... The Future!

So I thought I’d introduce you guys to some of the friends I made. I think you’ll be as surprised – and as excited – as I am.

Backyard Brains
Their motto is “neuroscience for everyone” – how cool is that? They sell affordable kits that let you experiment at home with the nervous systems of insects and other creatures. They gave a super-fun presentation where I got to help dissect a cockroach and send electrical signals through its nerves.

They build all kinds of cutting-edge tools that let home users study their brain activity, and even control machines and art projects with it. Their founder, Ariel Garten, has a great TED talk here – I’ve rarely met anyone else who was so excited to have weird new neuroscience adventures.

Deltaself and Dangerously Hardcore
Two blogs by the very smart Naomi Most – the first is about how scientific data is changing the way we all understand our minds and bodies; the second is about hacking your own behavior to stay healthier and live better.

Halcyon Molecular
Their aim is to put the power to sequence and modify genomes in everyone’s hands within the next few decades. They’re getting some huge funding lately, and lots of attention in major science journals.

Bonus – XCOR Aerospace
They’re building a privately-funded suborbital spacecraft for independent science missions. If there’s anybody who can help us all join the search for alien life in the near future, I bet it’s these guys.

So check those links out and let me know what you think. I’d love to get these folks involved in future videos, especially if you’re interested in any of them.

Beyond Perfection

If you continue to practice a skill even after you’ve achieved mastery of it, your brain keeps learning to perform it more and more efficiently, says a new study.

Believing you've reached perfection can lead you to engage in some...interesting...behavior.

As we perform a task – say, dunking a basketball or playing a sweet guitar solo – over and over again, we eventually reach a point that some psychologists call “unconscious competence,” where we execute each movement perfectly without devoting any conscious attention to it at all. But even after this point, our bodies keep finding ways to perform the task more and more efficiently, burning less energy with each repetition.

This story’s got it all – brain-hacks, mysterious discoveries, robots – but to put it all in perspective, we’ve gotta start by talking about this idea we call perfection.

“Practice makes perfect,” the old saying goes – but what’s this “perfect” we’re trying to reach? Isn’t it often a matter of opinion? What I mean is, how do we judge, say, a “perfect” backflip or a “perfect” dive? We compare it to others we’ve seen, and decide that it meets certain criteria better than those examples did; that it was performed with less error.

But where do these criteria for perfection come from? Well, some have said there’s a Platonic realm of “perfect forms” that our minds are somehow tapping into – a realm that contains not only “The Perfect Chair” but “the perfect version of that chair” and “the perfect version of that other chair” and “the perfect version of that molecule” and so on, ad infinitum. Kinda weird, I know – but a lot of smart people believed in ideas like this for thousands of years, and some still do.

Science, though, works in a different way: Instead of trying to tap into a world of perfect forms, scientists (and engineers and mathematicians and programmers and so on) work to find errors and fix them.

And it turns out that the human body is quite talented at doing exactly that. A team led by Alaa Ahmed at the University of Colorado at Boulder found this out firsthand, with the help of robots, the Journal of Neuroscience reports:

Seated subjects made horizontal planar reaching movements toward a target using a robotic arm.

These researchers weren’t interested in brain activity – instead, as the volunteers practiced moving the arm, the researchers measured their oxygen consumption, their carbon dioxide output, and their muscle activity.

As you might expect, the scientists found that as people got better at moving the arm, their consumption of oxygen and production of carbon dioxide, and their overall muscle activity, steadily decreased:

Subjects decreased movement error and learned the novel dynamics. By the end of learning, net metabolic power decreased by ∼20% from initial learning. Muscle activity and coactivation also decreased with motor learning.

But the volunteers’ bodies didn’t stop there. As people kept practicing, their gas consumption and output continued to decrease – and so did their muscle activation. In short, their bodies kept learning to move the arm with measurably less and less physical effort.

Though this study didn’t record any data from the subjects’ brains, it’s easy to see how this continual improvement is just one reflection of a very versatile ability. For instance, we know that when two neurons get really friendly, they become more sensitive to each others’ signals – and we also know that underused neural pathways gradually fade away, making room for new ones. Self-improvement impulses are woven deeply into our bodies – into our cells.

When I say that our brains and bodies are cities, I’m not just speaking metaphorically – you are, quite literally, a vast community – an ecosystem composed of trillions of interdependent microorganisms, each one constantly struggling for its own nourishment and safety.

And though your conscious mind is one part – a very significant part – of this great microscopic nation, it’s not the only part that can learn. At this moment, all throughout the lightless highways and chambers of your body, far below your conscious access, networks of cells are changing, adapting, learning, adjusting - finding errors and fixing them.

So, you can think about “perfection” all you want – but even at that magical moment when you achieve it, the multitudes within you are still hard at work, figuring out how to reach beyond that ideal.

What do you think they’re up to right now?

The Memory Master

A gene that may underlie the molecular mechanisms of memory has been identified, says a new study.

Some of us feel that "yellow" and "red" are open to interpretation...

The gene’s called neuronal PAS domain protein 4 (Npas4 to its friends). When a brain has a new experience, Npas4 leaps into action, activating a whole series of other genes that modify the strength of synapses – the connections that allow neurons to pass electrochemical signals around.

You can think of synapses as being a bit like traffic lights: a very strong synapse is like a green light, allowing lots of traffic (i.e., signals) to pass down a particular neural path when the neuron fires. A weaker synapse is like a yellow light – some signals might slip through now and then, but most won’t make it. Some synapses can inhibit others, acting like red lights – stopping any signals from getting through. And if a particular synapse goes untraveled for long enough, the road starts to crumble away – until finally, there’s no synapse left.

There’s a saying in neuroscience: “Cells that fire together wire together.” (And vice versa.) In other words, synaptic plasticity – the ability of neurons to modify their connectivity patterns – is what allows neural networks to physically change as they take in new information.  It’s what gives our brains the ability to learn.

In fact, millions of neurons are delicately tinkering with their connectivity patterns right now, inside your head, as you learn this stuff. Pretty cool, huh?

Anyway, synaptic plasticity’s not exactly breaking news – scientists have been studying it in animals like squid and sea slugs since the 1970s. Neurons in those animals are pretty easy to study with electrodes and a microscope, because a) the animals are anatomically simple compared to humans, and b) some of their neurons are so huge they can be seen with the naked eye.

Studying synapses in humans isn’t quite so simple, though. For one thing, most people wouldn’t like it if you cut open their brain and started poking around while they were alive and conscious – and besides, a lot of the really interesting stuff happens down at the molecular level.

That brings up an important point: though you normally hear about genes in connection with traits – say, a “gene for baldness” and so on – these complex molecular strands actually play all sorts of roles in the body, from building cells to adjusting chemical levels to telling other genes what to do.

That’s why MIT’s Yingxi Lin and her team set out to study the functions of certain genes found in the hippocampus – a brain structure central to memory formation – the journal Science reports. The researchers taught a group of mice to avoid a little room in which they received a mild electric shock, then used a precise chemical tracking technique to isolate which genes in the mouse hippocampus were activated right when the mice learned which room to avoid.

In particular, they focused on a hippocampal region with the sci-fi-sounding name of Cornu Ammonis 3or CA3 for short:

We found that the activity-dependent transcription factor Npas4 regulates a transcriptional program in CA3 that is required for contextual memory formation. Npas4 was specifically expressed in CA3 after contextual learning.

By “transcriptional program,” the paper’s authors mean a series of genetic “switches” – genes that Npas4 activates – which in turn make chemical adjustments that strengthen or weaken synaptic connections. In short, Npas4 appears to be part of the master “traffic conductor program” for many of the brain’s synapses.

Though they were pretty excited by this discovery (who wouldn’t be?) the researchers took a deep breath, calmed down, and double-checked their results, by testing memory formation in mice whose brains were unable to produce Npas4:

Global knockout or selective deletion of Npas4 in CA3 both resulted in impaired contextual memory, and restoration of Npas4 in CA3 was sufficient to reverse the deficit in global knockout mice.

In short, they make a pretty convincing argument that Npas4 is a necessary ingredient in a mouse’s ability – and probably our ability – to form certain types of new memories.

Exactly how that program relates to our experience of memory remains unclear, but it’s a promising starting point for fine-tuning future memory research. I don’t know about you, but I’d be thrilled to green-light such a project.

Stress Intervention

Scientists have discovered a way to shut down the brain’s “stress process” before it gets going, says a new study.

Stress, or just a very acute case of the munchies? It's hard to say.

By blocking the brain’s ability to manufacture certain chemicals called neurosteroids, researchers have managed to temporarily cut off a biological process crucial for stressful behavior – and for many stressful feelings as well.

Animals from amphibians all the way up to humans produce a hormone called corticosterone in their adrenal glands. Corticosterone levels become elevated under stress, and this hormone is a major ingredient in a number of stress-related biological processes, from feelings of nervousness to aggressive behavior.

Corticosterone does most of its direct work within a brain pathway known as the hypothalamic-pituitary-adrenal axis (also called the HPA or HTPA axis). To be honest, the word “pathway” is a bit of an oversimplification – the HPA is actually a whole set of neurochemical feedback circuits involved in regulating digestion, immune response, and mood, among other things.

The HPA’s activity is mostly regulated by a neurotransmitter chemical called gamma-Aminobutyric acid (GABA to its friends). GABA is typically an inhibitory neurotransmitter, which means it prevents electrochemical signals from being passed beyond a certain point. It often works closely with a neurosteroid called tetrahydrodeoxycorticosterone (THDOC), which helps its inhibitory effects spread even more widely throughout the HPA.

But when we come under stress, everything changes: the adrenal glands start cranking out extra-large doses of THDOC and sending them up into the HPA. And here’s where things get weird – those conditions trigger a certain electrochemical shift that causes GABA and THDOC to activate the HPA rather than inhibit it.

As the Journal of Neuroscience reports, the discovery of that neurochemical mechanism is the first half of a two-part breakthrough made Jamie Maguire‘s team at Tufts University:

We have identified a novel mechanism regulating the body’s response to stress by determining that neurosteroids are required to mount the physiological response to stress.

But how did they discover this mechanism, you ask? Well, since the team suspected that neurosteroidogenesis - the production of neurosteroids like THDOC – was a crucial component in stress-related HPA activation, they got a bright idea: they wondered if a drug that blocked neurosteroidogenesis might be able to stop the brain’s stress response before it could even get into gear.

As it turned out, they were right – they cut off the THDOC rush by administering a drug called finasteride – which you might’ve heard of under the brand name Propecia. Yep, the baldness drug:

Blocking neurosteroidogenesis with finasteride is sufficient to block the stress-induced elevations in corticosterone and prevent stress-induced anxiety-like behaviors in mice.

In other words, the researchers found that finasteride does more than just control stress – it blocks the chemical cascade that causes stress-related feelings and behavior. As far as they can tell, it prevents animals from experiencing stress at all - at least temporarily.

This has the potential to develop into a far more powerful treatment than benzodiazepines like Xanax and Ativan, which work by helping GABA inhibit more activity than it normally would. By contrast, a finasteride-like drug would make it almost impossible to feel stressed, even if you tried – meaning this drug might also be used to treat diseases like epilepsy and major depression, which have been linked to excessive activation of the HPA.

Right now, Maguire’s team is focused on isolating more of the exact neural connections that play roles in disorders like these. That means it may be a few years before this “wonder drug” becomes available. In the meantime, I wouldn’t recommend swallowing handfuls of Propecia when you’re feeling stressed – the drug needs to be applied in a pretty targeted way to make this work, which means a major part of pharmaceutical development will be the creation of an effective chemical delivery system.

Even so, it’s exciting to think that before long, depression and anxiety may be as easy to prevent as, say, polio and malaria are today. The thought’s enough to get my hormones pumping, anyway.

Chemical Parasites

A certain brain parasite actually turns off people’s feelings of fear by increasing levels of the neurotransmitter chemical dopamine, says a new study.

T. gondii, gettin' ready to blow your %@&#$ mind.

Toxoplasma gondii, a parasitic protozoan (a kind of single-celled organism), mostly likes to live in the brains of cats - but it also infects birds, mice, and about 10 to 20 percent of people in the U.S. and U.K. This might sound like science fiction, but plenty of microbiologists will assure you it’s very real.

In fact, T. gondii isn’t the only parasite that controls its hosts’ behavior – a fungus called Ophiocordyceps unilateralis makes infected ants climb to the highest point they can find, sprout fungal spore pods from their heads, then stay there and starve to death; at which point the spores are unleashed to recruit more ants for the fungus’s zombie army. Other microbes force spiders to weave cocoons for them, or make roaches lay immobile while larvae grow inside their bodies, then chew their way out. Um, yeah, so… nature is pretty frickin’ hardcore.

Anyway, back to the parasite at hand. Throughout the past few years, a University of Leeds microbiologist named Glenn McConkey has worked at the forefront of T. gondii research – in 2009, his team made the astonishing discovery that the microbe’s genome encodes instructions for producing dopamine: in essence, this bug is living cocaine, and it’s bending the minds of millions of people at this very moment.

And now, as the journal PLoS ONE reports, McConkey’s team has made a breakthrough that is, if anything, even more incredible: once the parasite has taken up residence in a brain, it triggers the production and release of dopamine at a much greater level than normal, causing infected animals (including people) to engage in impulsive, compulsive and/or fearless behavior:

In this study, infection of mammalian dopaminergic cells with T. gondii enhanced the levels of K+-induced release of dopamine several-fold, with a direct correlation between the number of infected cells and the quantity of dopamine released … Based on these analyses, T. gondii orchestrates a significant increase in dopamine metabolism in neural cells.

In short, by changing the electrochemical properties of dopaminergic neurons (those that deal with dopamine transmission and reception), T. gondii basically causes its host’s brain to shout “I’m awesome!” ceaselessly at top volume. You can imagine the havoc this wreaks.

If the host is, say, a mouse or a bird, impulsive and fearless behavior will typically get it gobbled up by a predator, which allows the parasite to move into a new host and spawn a new generation. But if the host happens to be a human being – well, there’s no telling what might happen. For one thing, studies have found a strong link between T. gondii infection and schizophrenia.

Thanks to Science, though, there’s hope – McConkey’s team is optimistic that these new results will help doctors diagnose T. gondii infections more quickly and accurately, and perhaps use dopamine antagonists – drugs that block dopaminergic activity – to fight some of the psychotic symptoms these crazy little guys cause.

So, I guess one big question remains: why the hell isn’t this story making front-page news? Your guess is as good as mine. Kinda spooky, isn’t it?

Enzyme Alarm Clock

Researchers have isolated a protein that sounds our biological clock’s alarm each morning, a new study reports.

Energy-saving tip: try replacing your alarm clock with a live rooster!

A gene known as KDM5A codes for an enzyme (i.e., a protein that increases the rate of a chemical reaction) called JARID1a. This enzyme acts as a switch that starts the biochemical process of waking us from sleep – like some kind of weird molecular rooster.

Here’s the background: scientists have known for years that levels of a protein called PER rise in the morning and fall toward nighttime. The level of PER in our bodies helps our cells know what time of day it is – higher levels tell us it’s time to be awake, while lower levels help make us sleepy. This wake/sleep process is known as the circadian rhythm or circadian cycle.

Two genes – known as CLOCK and BMAL1 – help raise levels of PER. When those levels reach a certain critical point in the evening, CLOCK and BMAL1 stop triggering a rise in PER levels – and as those levels drop, our heart rate, blood pressure, and mental activity slow down in preparation for bedtime.

But this research marks a new discovery: a specific enzyme that restarts the circadian cycle in the morning, telling CLOCK and BMAL1 to start raising PER levels again.

As the journal Science reports, a team led by Satchindananda Panda at Salk’s Regulatory Biology Laboratory collaborated with teams at McGill University and Albert Einstein College of Medicine to discover JARID1a’s role in the circadian cycle. The teams genetically engineered fruit flies to under-produce JARID1a, and these flies seemed to have no idea what time of day it was – they woke and slept at random hours, and took naps throughout the day… much like college students.

Human and mouse cells engineered to produce less JARID1a also produced odd levels of PER:

JARID1a increased histone acetylation by inhibiting histone deacetylase 1 function and enhanced transcription by CLOCK-BMAL1 in a demethylase-independent manner. Depletion of JARID1a in mammalian cells reduced Per promoter histone acetylation, dampened expression of canonical circadian genes, and shortened the period of circadian rhythms.

In other words, less JARID1a led to shorter circadian cycles of PER production in the cells.

But wait – there’s more! Panda and his team also discovered that JARID1a counteracts the effects of a protein called HDAC1, which acts as a molecular brake on CLOCK and BMAL1 each night. From this, the scientists reason that rising levels of PER tell HDAC1 to put the brakes on its own production as the night goes on, which would eventually allow JARID1a to restart the cycle by kicking CLOCK and BMAL1 back into gear, which would start raising PER levels again. Now how’s that for an intricate clock?!

The researchers confirmed this idea by inserting the JARID1a gene into the fruit flies that lacked it – and sure enough, JARID1a released the HDAC1 brake and put the flies on a normal circadian cycle.

Scientists hope this discovery will aid the development of certain types of drugs – for instance, as people age, their circadian cycles seem to shorten, and the researchers suspect this may have something to do with JARID1a. People with certain types of diabetes also tend to have out-of-whack circadian rhythms, so similar drugs might benefit them as well.

As for nocturnal college students and rockstars, though, I suspect the solution may not be quite so simple.

Optimistic Genetics

For the first time, scientists have pinpointed a particular gene variation linked with optimism and self-esteem, a new study reports.

A Genuine Scientific Image of the OXTR gene's G/G allele.

Two different versions – alleles - of the oxytocin receptor gene (OXTR) exist: an allele with the nucleotide “A” (adenine) at a certain location, and an allele with “G” (guanine) at that same location. Previous studies had found that people with at least one “A” molecule at that location tended to have heightened sensitivity to stress, and worse social skills.

But as the journal Proceedings of the National Academy of Sciences (PNAS) reports, a team led by UCLA’s Shelley E. Taylor were able to correlate certain alleles of OXTR with specific psychological symptoms:

We report a link between the oxytocin receptor (OXTR) SNP rs53576 and psychological resources, such that carriers of the “A” allele have lower levels of optimism, mastery, and self-esteem, relative to G/G homozygotes. OXTR was also associated with depressive symptomatology.

In other words, people who have either two “A” nucleotides, or one “A” and one “G,” at that specific location have lower-than-normal levels of optimism and self-esteem, and much higher levels of depressive symptoms, than people with two “G” nucleotides at that location on the gene.

Meanwhile, people with two “G” nucleotides at a certain location on their OXTR gene are more likely to be able to buffer themselves against stress. This is the most precise correlation between nucleotide differences and psychological traits that’s ever been discovered. And while this correlation isn’t a determiner of behavior, it does look like it’ll turn out to be an accurate predictor.

To figure this out, Taylor’s team studied the DNA from the saliva of 326 volunteers, and examined this data along with questionnaires each subject had completed. The questionnaires measured subjective feelings like self-worth, confidence, and positivity. The subjects also completed a set of questionnaires used to diagnose depression.

As is usual when stories like this – that is, about genes linked with certain traits – hit the press, there’ll probably be a flurry of articles with titles like “The Happy Gene,” making vague claims that the “gene for optimism” has been isolated. And that’s not what this study is about, at all – it’s about a connection between certain versions of a gene and the availability of certain psychological resources:

Some people think genes are destiny, that if you have a specific gene, then you will have a particular outcome. That is definitely not the case. This gene is one factor that influences psychological resources and depression, but there is plenty of room for environmental factors as well. Even people with the “A” variant can overcome depression and manage stress.

In short, what these allele differences mainly predict is a person’s susceptibility to certain psychological disorders if they encounter certain types of stress – not the likelihood that they’ll actually develop a given disorder.

It also remains to be seen what role, exactly, the neurotransmitter oxytocin, and its receptors, play in managing psychological troubles. As I’ve mentioned before, it’s been shown to lower stress and increase generosity – and it’s also involved in timing birth, encouraging hunger, and… heightening racist feelings.

Still, studies like this continue to being us more accurate and precise methods of diagnosing mental disorders – and even discovering if a person might be at risk for them. It’s also more evidence that our minds, like our bodies, are not all created equal – each of them is a unique neurochemical environment with its own thresholds of responsiveness.

So, next time somebody’s getting on your nerves, just tell them, “You better hope my oxytocin receptor genes are G/G alleles.” Take it from me: they’ll know exactly what you mean, and will probably back off and offer an apology.

Stress and Balance

Our responses to threatening situations depend on two fear-regulation circuits, a recent study shows.

"I wish this job wasn't so heavy on the glutamate."

A well-balanced sense of fear is crucial to our survival: too much, and we’d descend into panic attacks every time we were startled. Too little, and we might not react when survival is crucial. As it turns out, this balance is maintained by two opposing brain circuits, both involving corticotropin-releasing hormone (CRH) and its type 1 receptor (CRHR1).

The body releases CRH in response to stressful stimuli. This substance creates some pretty interesting effects in different parts of the brain – in areas like the forebrainhippocampus, and thalamus, it triggers the release of the excitatory neurotransmitter glutamate, which contributes to anxiety behavior.

But as a new paper in the journal Science shows, CRH helps with a completely different set of responses in the midbrain - it directly triggers the release of dopamine, which reduces fear and increases confidence. This means CRH and its type 1 receptors are involved in a self-regulating circuit that can both spread and reduce feelings of stress:

These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.

In other words, these two CRH-triggered systems exist in a delicate balance – and a disruption of that balance could lead to excessive fear reactions on the one hand, or to indifference on the other.

This means it’s probably time for psychiatrists to take another look at anti-anxiety drugs that target the brain’s CRH circuits:

The over-activity of the CRH system in patients with mood disorders is not general but probably limited to certain regulatory circuits in the brain, thus causing imbalanced emotional behavior.

This means that instead of just thinking of CRH as a “stress hormone,” we should probably be looking at these regulatory circuits as whole systems, and examining their interactions with one another.

So the next time you’re feeling panicky, try to remind yourself that it’s just your glumatergic neurons acting up – and those lovely dopaminergic circuits should kick in any second.

Diff’rent Vesicles

A new discovery shows that the rules of synaptic transmission are very different from what we’d thought.

A synapse, blissfully unaware of the VAMP7s lurking in its midst.

In each neuron, tiny sacs called vesicles store neurotransmitter chemicals, and help transport them to other neurons. For decades, scientists had thought all the vesicles of a particular neurotransmitter were more or less identical – but now, they’ve discovered that only one set of vesicles are marked for transmission, while a much larger set lay mysteriously dormant.

What causes these differences, you ask? A protein with an awesome name:

We now find that the v-SNARE tetanus toxin-insensitive vesicle-associated membrane protein (VAMP7) differs from other synaptic vesicle proteins in its distribution to the two pools, providing evidence that they differ in molecular composition. We also find that both resting and recycling pools undergo spontaneous release, and when activated by deletion of the longin domain, VAMP7 influences the properties of release.

In other words, the presence of VAMP7 in a vesicle is an indicator of whether it’ll be released or not. This overturns the previous assumption that some vesicles get transmitted because – more or less – they’re in the right place at the right time. But now we know that vesicles don’t just get “discovered” like aspiring actresses – each one is born for its job, just as some of us are born to ride, run, or be wild.

As a paper published in the journal Neuron reports, a team led by UCSF’s Robert Edwards tagged various proteins with glowing (bioluminescent) molecules found in jellyfish. They found that VAMP7 levels are high in the resting pool of vesicles – the one that stays inside the neuron – but much lower in the recycling pool, which contains the vesicles that get transmitted, then recycled for later use.

Since the resting pool of vesicles can be 80 percent larger than the recycling pool, Edwards is sure it plays a significant purpose – but no one has any idea what that purpose is yet:

Resting vesicles are involved in a separate not-well-understood process in which neurons spontaneously release vesicles, which may help them adjust the types of connections they make with each other as well as the strength of those connections.

Since these vesicle differences may apply to all neurotransmitters in all neurons, it looks like we’ll need to correct some major misunderstandings about how the nervous system works. For one thing, we’ll probably need to reassess how we understand brain diseases whose symptoms stem from synaptic transmission problems.

It’s going to be really interesting to see what future research tells us about these resting vesicles, and what kinds of secret missions they get sent on when they’re not resting.

Pain on the Brain

Men and women experience pain in different ways, a new study shows.

"Aaaagh, my KORs are killing me!"

The behavior of opioids – chemicals that suppress pain – differs between men’s and women’s bodies. This is because the three main types of opioid receptors in the brain and spinal cord interact very differently, depending on whether their owner is a man or a woman.

See, scientists have known for years that certain kinds of narcotic analgesics – a certain class of pain relieving drugs – are much more effective on women then on men. It was hard to understand why, though, because both men and women have mu (MOR), delta (DOR), and kappa (KOR) opiate receptors – the three main kinds – and these receptors work in essentially the same way in either gender.

But now, scientists have found that the spinal cords of female animals have almost five times as many kappa-mu heterodimers - complex molecules formed by combining KORs and MORs (commonly called KOR/MOR heterodimers) - as those of males. And not only that – the number of KOR/MOR heterodimers climbs four times higher when a woman’s body is pumping with estrogen and progesterone – two hormones crucial for regulating female body chemistry:

Spinal synthesis of estrogen is critical to the processes [of forming and using KOR/MOR heterodimers], and blockade of either estrogen receptor (ER) α-, β-, or G-protein-coupled ER1 or progesterone receptor (PR) substantially reduces KOR/MOR and eliminates mediation by KOR of spinal morphine antinociception.

In other words, a squirt of estrogen causes a sharp increase in the number of KOR and MOR receptors that get formed. This is a Big Deal, because some previous research suggests that in men, KORs and the chemicals that activate them may actually promote pain – and that their attachment to a MOR converts them to part of a pain-relieving system:

The research suggests that kappa-mu opioid receptor heterodimers could function as a molecular switch that shifts the action of kappa-opioid receptors and endogenous chemicals that act on them from pain-promoting to pain-alleviating.

To figure out what was going on with all these receptors, a team led by Alan Gintzler, a SUNY biochemist, first did some research to show that KOR and MOR opioid receptors join to form KOR/MOR heterodimers, the Journal of Neuroscience reports. This research was the first step toward understanding how these receptors interacted in the body’s pain system.

For this new study, though, the scientists injected estrogen and progesterone into the spinal cords of test animals, and determined that both chemicals were critical for the formation or KOR/MOR heterodimers, and these heterodimers’ activity in suppressing pain, as opposed to spreading it.

This discovery could go a long way toward explaining why certain pain-suppressant drugs that target MORs and KORs – such as pentazocine and nalbuphine - work well on women, but poorly on men: in spinal cords that lack the KOR/MOR heterodimer, the drugs might be activating the lonely little KORs, which – without their MOR friends, would help promote pain instead of relieving it. How rude of them.

Anyway, this new data looks like it’ll provide some encouraging ideas for future pain relief research:

The activation of the kappa-opioid receptor within the kappa-mu-opioid receptor complex could provide a mechanism for recruiting the pain-relieving functions of spinal kappa-opioid receptors without also activating their pain-promoting functions.

The researchers also point out that doctors should talk with women about where they are in their menstrual cycle before prescribing them medications like these – when estrogen and progesterone levels drop, pain relievers might turn into pain promoters.

So the moral of the story is, if you’re a guy (or a women who’s low on estrogen), some things really are gonna hurt me more than they hurt you.


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