Wednesday, March 26, 2014

Naked Mole Rats Don’t Feel The Burn

Biology concepts – thermoregulation, heat sensing, TRPV1, evolution, neurotransmitters, birds, ectothermy, diet-induced thermogenesis

BBC television has a very nice Sherlock Holmes show
running nowadays, but it has ticked off some mental
health professionals. Sherlock describes himself as a
high functioning sociopath. I have read several angry
letters from those in the profession saying that he
should stop doing so, he is using a mental disorder as
an excuse for just plain rude behavior.
Diseases of the mind are often more bizarre and more tragic than diseases of the body. Medicine and psychiatry use different terminology; terms of the mind are often less specific than terms of anatomy and physiology. For instance, what’s the difference between a psychopath and a sociopath?

There is an argument currently raging as to whether there is any difference between these two labels for anti-social personality disorder. The major similarity is in self-centered actions without remorse for doing wrong to others. The differences may lay in organization. Psychopaths are impulsive while sociopaths may plan things out and use charm to conceal themselves. Others say psychopathy is genetic and sociopathy is learned. But both groups are fine with breaking rules.

This blog has used rule breakers as models for explaining biology concepts, just as medicine uses them as ways to find corrections for when things go wrong. If one animal could be the poster child for rule breaking in biology, it would have to be the naked mole rat (Heterocephalus glaber). There are so many rules that this animal breaks or ignores, it makes one wonder if it's a sociopath or a psychopath.

In truth, the naked mole rat has no motivation for breaking rules. It’s merely a reflection of the evolutionary forces that its ancestors felt, adaptations to pressures over a long period of time. If rules had to be broken, so be it. It’s evolution that’s the psychopath.

The broken rules we are concerned with in this post relate to TRPV1. The capsaicin of chili peppers does not inflict pain on naked mole rats! H. glaber TRPV1 binds capsaicin just fine, it just doesn’t result in pain. The difference comes in the spinal cord. A 2008 paper shows that the connections from the TRPV1 expressing nociceptive neurons to those neurons that would convey the signal to the brain are different in naked mole rats, and the additional pathways result in a loss of the pain signal.

This isn’t just a pile of naked mole rats that someone
dumped out of a bucket. This is how they sleep. They
use each other to keep warm because they are cold
blooded. A cold-blooded mammal? Well, I never
imagined. But they break more rules – they live much
longer than other mammals, they don’t get cancer,
and they have a queen like in bee hives. Drum roll
please – the naked mole rat was named the vertebrate
of the year for 2013 by Science magazine.
There’s no inherent advantage in altered TRPV1 signaling via capsaicin for H. glaber; they don’t eat chili peppers. But remember that TRPV1 is activated by more than just capsaicin, so perhaps the advantage lies in stopping some other activation of TRPV1 and it just so happens that it also stops capsaicin–induced pain.

One of those other TRPV1 activators is acid. We said that a pH below 5.5 activates TRPV1 and a pH between 5.5 and 6.5 makes TRPV1 more sensitive. This is pertinent for naked mole rats because they live entirely below ground. Their tunnels are high in CO2 from all their exhalations. Excess CO2 in the tissues causes an acidosis, a low pH situation. If the H. glaber TRPV1 acted as it does in every other mammal, then naked mole rats would be in constant pain.

New research (2011) shows that the acid does indeed make naked mole rat TRPV1 channels open just as capsaicin does, but the neurons don’t fire. Acid suppresses a certain sodium channel downstream of TRPV1. Normally, the calcium influx mediated by TRPV1 activates the Nav1.7 sodium channel, and the neuron is depolarized and fires. But acid destabilizes the Nav1.7 channel and there is reduced firing.

This suppression occurs in all mammals, but it is a much stronger suppression in naked mole rats, because two amino acids are changed in their version of Nav1.7. Now we have two TRPV1 activators (capsaicin and acid) that no longer result in pain, but for two different reasons. Is there more?

Substance P is a neurotransmitter and modulator
that is important for pain signaling, but it also works
in vomit regulation. In the medulla of the brain lies
the vomit center, and it uses substance P to induce a
reversal of the motion of the GI muscles that usually
moves food through the GI tract. A spike of substance
P in the wrong place, and here comes supper for a
return engagement.
A neurotransmitter called Substance P is also important in TRPV1 pain signaling. Are you getting the idea that this is a complicated system - I sure am. It turns out that naked mole rats don’t make substance P (2010). Now we have three different reasons that naked mole rats don’t transmit pain signals via TRPV1. This is an evolutionary overkill, but it makes the mole rats able to live where they live without fear of unnecessary pain.

But the question remains, did the mutations in TRPV1 signaling permit H. glaber to move permanently underground, or did living underground put pressure on the naked mole rat to adapt through TRPV1 mutations? It’s hard to tell which was the cart and which was the horse.

The naked mole rat’s lack of pain signaling via TRPV1 may help us humans. The more we know about the mechanisms of H. glaber TRPV1 action, the better we can design pain killers for ourselves. Exceptions can often be our savior.

Another rule that naked mole rats break is that they are cold-blooded (ectothermic) mammals. We know that TRPV1 is important in heat sensing, so does having altered TRPV1 pathways mean that the naked mole rat can’t thermoregulate and that’s why it’s ectothermic?

The rats can still probably sense heat. Remember that there are other TRPV proteins that are important in heat sensing; nothing says these aren’t functioning just fine. For that matter, there is no evidence that the TRPV1 of H. glaber is defective in heat sensing. It just doesn’t result in a pain sensation.

And it would be wrong to believe that ectotherms don’t need to sense heat. It may be even more crucial for ectotherms. Cold-blooded animals must find the heat in their environment and soak it in – but not too much. This means they must be experts at knowing how much heat they have and where they can find more.

Ectotherms also need to know where the shade is, so they can cool off if they get too hot. To prove this, we know that reptiles with mutated thermosensors don’t shuttle between warmer and cooler areas and can’t maintain a satisfactory physiologic temperature.

As weird as the naked mole rat is, birds also seem to break the rules when it comes to TRPV1; they can order their food spicy as well. Why is it significant that birds don’t sense capsaicin as burning pain? Remember that chilies are a group of plants with fruits. Those plants have evolved capsaicin to inhibit herbivorous predators and fungal infections, as we talked about last week. Now we have the fact that birds don’t react to capsaicin. How are these linked?

Squirrels are the bane of every backyard birder’s
existence. They eat ten times as much feed as the
birds, and they can find some creative ways to
reach the bird food. Try adding pepper flakes to
the bird feed, squirrels feel the burn, but your
song bird visitors won’t.
The answer is seed dispersal. It is important that chili peppers are consumed and the seeds are spread. This is crucial for the survival of the plant species. But if the fruits are spicy and there is avoidance of same by most animals, how will the seeds be spread? Well, there better be some animals that don’t react to capsaicin – birds.

The TRPV1 of most birds doesn’t have a vanilloid binding site. The channels work for heat sensing and do react to acids, but there is no activation by capsaicin. Since there is no capsaicin binding site, birds only taste the peppers, they don’t get the burn. It's possible that they taste the many different vanilloid compounds, so peppers may taste a little like vanilla to birds.

I still have one question – there's certainly a reproductive advantage for peppers when birds don’t sense capsaicin (for seed dispersal), but where is the advantage for birds? And how could pepper plants force the evolution of a different TRPV1 in birds? One possibility - maybe birds evolved a different TRPV1 to take advantage of a food source that other animals avoid. No competition for food would definitely be a reproductive advantage for birds.

But this explanation has exceptions as well. The TRPV1 of chickens is activated by capsaicin. It is weak, taking 3-4 times more capsaicin to get a reaction, but it does work. So if you own chickens, don’t give them very spicy feed. Ducks on the other hand, have a TRPV1 that doesn’t sense capsaicin or heat.

Some foods are considered negative calorie items. They
supposedly cost more to digest than the energy they
provide in calories. I’m not sure if I believe that all these
foods are negative calorie foods. If they were, there would
be a lot of starving vegetarians. If not dead, they would be
awfully weak and tired.
You can inject huge amounts of capsaicin extract into the veins of ducks without them having any kind of a thermal response. Since TRPV1 senses heat and then initiates a cooling process, capsaicin in the blood will result in too much cooling – a hypothermia. In chickens this hypothermia occurs, but not in ducks.

So thermosensing must be important. Even in most animals that don’t respond to capsaicin, their TRPV1 still works in thermoregulation. I can give you an idea of how intricate and detailed this thermoregulatory system is by talking about digesting spicy food. Your body uses energy and metabolism to digest the food you eat. This energy use produces heat as a byproduct, and warms you up a bit. This is called diet-induced thermogenesis. Celery is an excellent diet food because the energy you use to digest it is the same or more than the calories in the celery itself.

For some reason, spicy foods increase diet-induced thermogenesis; you expend more energy and heat up more when eating spicy foods than when eating the same foods without the capsaicin. Recent evidence indicates that including capsaicin and medium chain triglycerides in a meal will increase diet-induced thermogenesis by over 50%. This combination also makes you feel full sooner and therefore decreases overall caloric intake.

The spice also makes you use more energy for digestion, but it also makes your body think it is warmer than it is, so it tries to cool down. Cooling down also takes energy, so eating spicy food really does burn more calories - maybe because fat takes more energy to digest and capsaicin is a lipid-like molecule.

Some weird products include capsaicin for the supposed health
benefits. Here are capsaicin drinks. Including capsaicin in a diet
will help you eat less, but I am thinking it may be because you
just get tired of sweating and feeling like your mouth is on fire.
Another recent study shows that the decrease in energy your body expends when you diet (an evolutionary adaptation to try and maximize fat reserves) is prevented by consuming capsaicin. So you burn more calories with spicy food and your body doesn’t even realize your dieting. Somebody should try breeding a capsaicin-packed celery stalk.

Next week we'll see that TRPV1 is even more amazing. Not every spicy food contains capsaicin, there’s mustard, black pepper, horseradish, ginger, cinnamon, etc. Some of these even make your capsaicin seem spicier.

Smeets AJ, Janssens PL, & Westerterp-Plantenga MS (2013). Addition of capsaicin and exchange of carbohydrate with protein counteract energy intake restriction effects on fullness and energy expenditure. The Journal of nutrition, 143 (4), 442-7 PMID: 23406619

Clegg ME, Golsorkhi M, & Henry CJ (2013). Combined medium-chain triglyceride and chilli feeding increases diet-induced thermogenesis in normal-weight humans. European journal of nutrition, 52 (6), 1579-85 PMID: 23179202

Smith ES, Omerbašić D, Lechner SG, Anirudhan G, Lapatsina L, & Lewin GR (2011). The molecular basis of acid insensitivity in the African naked mole-rat. Science (New York, N.Y.), 334 (6062), 1557-60 PMID: 22174253

Park TJ, Lu Y, Jüttner R, Smith ES, Hu J, Brand A, Wetzel C, Milenkovic N, Erdmann B, Heppenstall PA, Laurito CE, Wilson SP, & Lewin GR (2008). Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber). PLoS biology, 6 (1) PMID: 18232734

Smith ES, Blass GR, Lewin GR, & Park TJ (2010). Absence of histamine-induced itch in the African naked mole-rat and "rescue" by Substance P. Molecular pain, 6 PMID: 20497578

For more information or classroom activities, see:

Naked mole rat –

Substance P –

Seed dispersal –

Diet-induced thermogenesis -

Wednesday, March 19, 2014

Maybe We Do Taste The Burn

Biology concepts – capsaicin, TRPV1, heat sensing, thermoregulation, taste, ligand

Eating spicy food can seem like having fire in your mouth.
Interestingly enough, some people do that. Fire eaters do
not use “cold flames” or anything in their mouths other
than spit. One fire eater famously said that the key to being
a good fire eater is the ability to endure pain.
Early in our dating experience, my wife and I visited a Thai restaurant in our old college town. As part of the ordering process, you were allowed to tell them just how hot you would like your food. Eager to impress, I asked for the hottest they had. Big mistake.

Not long after my first bites, the burn started in my mouth. I began to sweat and my eyes watered. My nose ran and the area around my mouth and nose turned red. I looked like I was attending my best friend’s funeral on a sunny 110˚F afternoon. This was not the impression I was hoping for.

Little did I know that I was demonstrating one of the body's most amazing receptors, TRPV1, the capsaicin ion channel. To this day, even though I now appreciate the biology of the experience, I have nightmares where little Thai chilies grow large: towering over the child-like me on a dream playground, the peppers twist my arm, take my lunch money, and give me a wedgie.

TRPV1 stands for the transient receptor cation channel subfamily V (vanilloid) member 1. That’s a mouthful; let's see if we can make it easier. Transient means that it is not activated all the time, something has to come along to activate it. Cation channel means that when activated, the receptor allows for the flow of positive ions (cations) from the outside of the cell to the inside.

There are many cations in the body, but TRPV1 is especially good at letting calcium (Ca++) ions flow into the cell. Calcium movement is at the heart of many of the functions we will talk about in the coming posts.

Here all the known members of the human TRP family,
including all the subfamilies. There six members of the
TRPV subfamily; our discussion will be about TRPV1.
The lone member of the ankyrin subfamily, TRPA1 will be
a big player in the weeks to come. Likewise, TRPM8 is a
cold receptor and we will talk about it extensively. I don’t
know much about the P, C, and ML subfamily members.
The fact that TRPV1 is a channel means that it is not a one to one ratio. Activation of the channel is like opening a gate, where many ions will flow through. Finally the fact that it is a subfamily means that there are many channels that are similar to it and this one is activated by molecules that look like vanillin, an alkaloid fatty acid - capsaicin is a vanilloid compound.

TRPV1 is expressed on many cell types, but is most often found on nociceptive (pain sensing) neurons of the class-C type (these are small and respond to only some types of noxious stimuli). The class-C nociceptive neurons are found in the peripheral nervous system, like in your skin and mucosa, but also in the central nervous system, especially those parts that interpret pain signals. Those TRPV1 receptors located in tissue cells and neurons can lead to some bizarre functions, and we will talk about those in later posts.

TRPV1 is a primarily a heat sensor, but there are other heat-sensing members of the TRPV subfamily. TRPV3 is activated by temperatures around 33˚C to 39˚C, while TRPV4 senses temperatures in the 27-34˚C range.

Since TRPV1 is also a pain transducer, it senses heat that would cause pain, specifically, temperatures above 43˚C (110˚F). Because TRPV1 transduces (changes) the heat into a signal for pain, you pull your hand back when you stick it in hot water because it is painful. If you didn’t, the water could do damage to your tissues; the pain from TRPV1 activation is an effort to prevent tissue damage.

Both Adelta and C neurons carry pain signals to the
brain. Adelta nerves are large than C fibers, and they
transmit information much faster. A delta fibers
signals travel about 5-35 meters/second, while
C fibers depolarize at only0.5 to 2 mm/s. However,
the signal is also shorter lasting. C fibers give a longer
sense of pain, called second pain. C fibers also carry
signals of chemical pain, while Adelta fibers do not.
The signals from TRPV1 travel up several nerves to the brain, but seem to involve the trigeminal nerve centers most often. Noxious (noxa is Latin for harm, same root as for nociceptive) neural signals don’t travel to the gustatory centers of the brain. This is why it’s said that you don’t taste capsaicin, you merely perceive it as burning heat and pain. But this may be a misconception.

Capsaicin is a vanilloid type molecule. So is vanilla. You taste vanilla, so why not capsaicin too? Supertasters seem to have more neurons with TRPV1 channels, so they taste more and they sense more capsaicin. Some drugs that interfere or kill taste buds also make hot foods not so spicy. So who’s to say we aren’t tasting capsaicin?

During my thai chili/dating incident, I noticed that I was only getting the pain and the burn, I wasn’t tasting my food much. It might have been due to the excruciating pain ruining my dining experience, or it might be that capsaicin can suppress some tastes.

A 2009 paper showed that mice that were fed capsaicin seemed to crave sugar more strongly. The idea we talked about during our taste posts was that if you taste it less, you need more to satisfy a craving. So perhaps the mice tasted less sugar after having been fed capsaicin.

This is supported by a 2010 study that showed that TRPV1 receptors are expressed in taste receptor cells of the circumvallate papillae, and are often co-localized (are on the same cell) with sweet or bitter taste receptors. The authors hypothesized that activation of TRPV1 by capsaicin modulates taste receptors to suppress (not eliminate) sweet and bitter tastes.

Some high mineral foods can give a metallic taste in
the mouth, but more often this is the result of metals
on their own or disease. Gum disease is common cause,
but drugs are a more common cause. Some uncommon
antibiotics give a metallic taste as do many cancer drugs.
Lithium, used to treat bipolar disorder, tastes like
metal because it is a metal.
In addition, a 2009 study talked about how some compounds are sensed as metallic tastes, and these are mediated, in part, by TRPV1 signaling. This is part of the reason why humans and other animals avoid heavy metal tastes and why they can be uncomfortable as well. High concentrations of artificial sweeteners can give an uncomfortable metallic taste, again linking TRPV1 with sweet taste receptors.

It seems that even if we don’t taste capsaicin itself, it can change what it is we do taste. So capsaicin is involved in our sense of taste. But perhaps we can go further. TRPV1 knockout mice (genetically engineered mice with no TRPV1 receptors) still have changes in taste for sweet, bitter and metal. So at least some of the capsaicin signaling is occurring via the taste receptors themselves – and we could call that tasting capsaicin.

Let the tasting arguments begin, and you might want to include the following in the discussion. If TRPV1 activation by heat results in the same signaling as with capsaicin, does it follow then that we taste heat?

Let’s talk more about TRPV1 as a noxious heat sensor. When activated by high heat, TRPV1 signals your brain (particularly the hypothalamus) that your body is too hot. Your brain then activates mechanisms to increase the release of heat from your body to the environment. This might include sweating, breathing faster… things like that.

When you eat spicy foods, the message to the brain via TRPV1 is exactly the same. The capsaicin tricks your brain into believing your body is overheated, and kicks in the cooling mechanisms. This is why people in hot regions of the world eat spicy food - it helps cool them off. The truth of this comes from those same TRPV1 knockout mice. They never get the signal to cool the body because they never sense that they are too hot. Therefore, these mice tend to suffer from hyperthermia (hyper = excess, and thermia = heat). People with TRPV1 problems are hyperthermic too.

On top is a cartoon demonstrating the key in lock model for
protein/ligand interactions. On the bottom is a cartoon
showing the difference between protein denaturation by heat,
and protein conformation change by heat. TRPV1 can undergo
the first and third scenarios.
This is today's exception - that TRPV1 is activated by such different mechanisms (heat and capsaicin), but that the activation results in exactly the same signaling. The receptor is a protein, and we have seen many times that receptors are activated by other molecules through the lock and key mechanism. The shape of the ligand (the molecule that binds or ligates to the receptor) matches exactly a pocket in the receptor, so they fit together like a key in a lock - and the receptor function is unlocked.

But how can heat fit into a ligand binding site on the TRPV1 ion channel? It’s just a physical state, not a solid object. New research is showing that the heat changes the shape of TRPV1, and this conformation (con = together, and form = shape) change activates the ion channel. In isolated receptors with no extra proteins around, heat alone was enough to activate the receptor, so the conformation change is all that is needed to have the ion channel open.

Heat changing the shape of a protein is common; that’s what happens when you cook food. Roasting, pan frying, poaching, toasting - in every kind of cooking the protein becomes denatured (de = without, and nature = form). Proteins lose all shape and function when cooked. In the case of TRPV1 and noxious heat, the protein changes conformation, but is not denatured; therefore, it can be activated by the heat.

On the left is a myotonic arm and hand. This is a state of hyper-
excitation. One contraction leads to repeated action potentials
and waves of contraction. The action potentials occur in the
muscle fibers, not in the neurons that lead to the muscle. On the
right is paramyotonia. You see the hand/arm is in a pan of cold
water – well, take my word for it, it’s called. This is the opposite
of myotonia, in this case the relaxation is extended and the
muscle won’t contract. It can be brought on by cold.
A protein that is thermosensitive is amazing, but apparently it has happened more than once in history. There is a condition in some humans (maybe other animals, but we haven’t asked them) where heat can induce myotonia (prolonged contraction) and cold can induce paramyotonia (prolonged relaxation, nearing paralysis). In 2000, a group in Japan described a family in which this condition is a dominantly-inherited, genetic disease.

A certain sodium channel (SCN4A) is mutated and the mutation makes the sodium channel thermosensitive. At higher temperatures, the protein changes shape and makes it harder for the muscles to relax. For example, a person with myotonia might take a longer than normal time to release their grip on an object. In cold temperatures, SCN4A changes to a different shape and is almost non-functional, so relaxation is hard to overcome and contraction of a muscle is slow and weak.

In this case the mutation has an unwanted result, but one can see how TRP channels probably evolved from similar mutations. Once again, evolution shows itself to be non-directed; mutations can be good, bad, or indifferent -  they only survive through generations if they confer an advantage. At some point, being able to sense heat via TRPV channels became advantageous. It must have been early in evolution, because yeast, insect, higher animals, and even plants have mechanisms to sense heat.

Next week, let’s meet a couple of animals that just won’t play by the rules. Heat and capsaicin don’t act on their TRPV1 the way it does for everyone else.

Cao E, Cordero-Morales JF, Liu B, Qin F, & Julius D (2013). TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids. Neuron, 77 (4), 667-79 PMID: 23439120

Costa RM, Liu L, Nicolelis MA, & Simon SA (2005). Gustatory effects of capsaicin that are independent of TRPV1 receptors. Chemical senses, 30 Suppl 1 PMID: 15738113

Sugiura Y, Aoki T, Sugiyama Y, Hida C, Ogata M, & Yamamoto T (2000). Temperature-sensitive sodium channelopathy with heat-induced myotonia and cold-induced paralysis. Neurology, 54 (11), 2179-81 PMID: 10851391

Riera CE, Vogel H, Simon SA, Damak S, & le Coutre J (2009). Sensory attributes of complex tasting divalent salts are mediated by TRPM5 and TRPV1 channels. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29 (8), 2654-62 PMID: 19244541

For more information or classroom activities, see:

Capsaicin –


Thermoregulation –

Myotonia/paramyotonia -

Wednesday, March 12, 2014

Are Chilies Spicy, Hot, Or Piquant?

Biology concepts – fruit, spice, capsaicin, Scoville heat units, TRPV1 heat sensor, taste, true berry

Preface: I had intended on finishing our series on taste sense with a single post on how spicy foods are a taste exception. But the information and exceptions kept pouring out of the literature; every turn gave me a new feature to look at in more depth. So, instead of a single post, here is the first in a series on spicy foods and how our sensation of spiciness or coolness is related to many biological concepts and functions. We experience these daily without ever thinking about them, but the exceptions will show just how inventive life can be.

Here is the fruit of the jalapeno pepper. It is formed from
a single ovary, where the pericarp (ovary wall) is made up
of the exocarp, mesocarp, and endocarp. The placenta is
also called the septum, and on the sides of it are the
capsaicin glands.
Quick, name the spiciest fruit you've ever tasted. Spicy fruit? Is this some bizarre candy commercial? Nope. I bet we've all had a spicy fruit – how about jalapeno fruits, or habanero fruits?

Chili peppers are indeed considered fruits. They are true berries, but they are the exception in berries, as they don’t have a fleshy middle; they're mostly hollow. They form from a single ovary, and the chili is the entire ovary wall ripened into an edible form called a pericarp.

The capsaicin (the dominant spicy molecule in chili peppers) is present in all the fruit structures, but there are higher concentrations in the seeds and the ribs (septa) that hold the seeds to the inner face of the fruit wall. Even the hottest peppers have tastes other than spice, but it's really a matter of how much capsaicin is packed into the flesh that determines the overall sting of the pepper.

Chili peppers got the name "pepper" because they were spicy, like the black pepper plant, but there's no botanical relationship between these two kinds of plants. Chili peppers are from the genus Capsicum. There are about 27 species in the genus, but each species comes in several varieties – bell peppers and jalapenos come from the same species. The Capsicum genus is just one of the 90 or so genera in the family Solanacae, the nightshades. This is a diverse family of plants, including potatoes, tomatoes, tobacco, petunias, and even some trees.

Fusarium fungi preferentially grow on fruits. They are
the primary cause of pre-dispersal seed mortality. Humans
are susceptible to infections with the fungus, and eating
bread made from contaminated grain is lethal. In the
2000’s the US proposed using fusarium mycotoxins as
a way of killing drug crops in South America.
Why would plants make their fruits, leaves, and stems spicy? As a defense, I would guess. It seems that this discourages many an herbivorous predator. A 2008 report shows that Fusarium fungus has a hard time growing on plants that produce capsaicin, but easily infects those that do not.  The development and increase in capsaicin levels is a result of evolutionary pressures applied by fungal chili plant pathogens.

But on the other hand, why put the hot stuff in the fruits? Don’t you want animals to eat the fruits and then spread the seeds around in their feces? Isn’t that the point of making a fruit – to entice some animal to disperse your seeds? It makes one wonder.

For what ever reason they do it, there's a new king of the spicy fruits: the Carolina Reaper. Bred in South Carolina specifically to be the world’s spiciest pepper, the Reaper weighs in at a whopping 1.6 million Scoville heat units. Here is a video of some nut downing one, but be careful – there's vomiting involved. That should give you some idea of this pepper’s powerful potency.

What’s a Scoville heat unit (SHU), you ask? In the test originally designed by pharmacist Wilbur Scoville in 1912, this number referred to the number of squirts of sugar water needed to extinguish the flames in your mouth after you bite a pepper. Later, SHU became more scientifically defined as the number of dilutions needed to make a given mass of chili flesh lose its sting. But this was still a subjective measure, with different people reporting different dilutions as necessary.

Born in January 1865, Wilbur Scoville’s middle name was Lincoln,
after the President who would be assassinated later that same year.
He was a pharmacist at Parke Davis when he devised the Scoville
Organoleptic Test for hot food spice, but he was famous for other
reasons in pharmacy. He wrote several textbooks that were used up
until the 1960’s. On the right is the madness Scoville wrought. This is
the Carolina Reaper, bred only to be hot. It is grown only in one plot
in South Carolina, appropriately named Pucker Butt Farms. Notice
that the person is not wearing gloves. I really hope he didn’t rub
his eyes or pick his nose after this.
Nowadays, scientists use a laboratory test called high performance liquid chromatography (HPLC) to measure the amount of capsaicin in each sample. One part capsaicin per million parts pepper is equal to 15 Scoville units (or approximately 18 µM capsaicin/SHU). Pepper eaters agree that the HPLC method gives SHU values about 20-40% below those of the old methods.

The 1.6 million SHU for the Carolina Reaper is about 100,000 units more than the previous record holder, the Trinidad Morgua Scorpion pepper, which is still the spiciest pepper that grows in the wild. Take note that the value is the average for a batch of the peppers grown at the same time at the same place, but the SHU will vary from pepper to pepper.

For the Reaper, at least one individual pepper has been measured at more than 2.2 million SHU, and a Morgua Scorpion individual has come close to this at 2.01 million SHU. The individual differences can come from slight variations in environmental and soil conditions between plants.

A 2013 study found that temperature will affect capsaicin levels. For several pepper cultivars, as the growing temperature increased, so did the capsaicin levels. But the effect was the opposite in jalapenos; higher growing temperatures led to lower capsaicin levels.

The cause of all this spiciness – capsaicin. It's not a protein, but is more aptly described as a nitrogen containing fatty acid – yet another amazing fat. It is one of many compounds called vanilloids, named after one member, the vanillin molecule that gives us vanilla taste and aroma.

Capsaicin is an alkaloid fatty acid. The long hydrocarbon
tail makes the molecule fat soluble but water insoluble.
It also adds to the molecular weight and reduces its
volatility. This is lucky, nobody wants a snoot full of
capsaicin. Some people live for the hot food, enough to
wear it as a permanent marker on their body.
The fact that capsaicin is a fat is pertinent to eating hot peppers. Chemists say, “Like dissolves like,” meaning that a fat will be soluble in fat, but not in water. So when eating spicy foods, remember that drinking water isn’t going to douse the fire no matter how much you drink. Alcohol will work, but beer doesn’t have enough alcohol to make a difference.

The best bet to take the sting out of your curry is whole milk. Why? Because whole milk has sufficient fat to draw the capsaicin off your tongue, and milk also contains a protein called casein. Casein is lipophilic (lipo = fat, and philic = loving), so it will take the capsaicin off your tongue too. You won’t look very manly, but at least you’ll survive.

Many “professional” chili eaters don’t worry about the manly thing at all. After proving how strong they are by eating a ghost pepper or a Carolina Reaper, they will often fill their mouth with Cheez Whiz, or even shove cheesecake up their nose to try and placate their burning nasal membranes!

Pure capsaicin is rated at 16 million SHU, so even the hottest Carolina Reaper is only 1/8 as spicy as theoretically possible. Of course there is no way you could make a pepper that contains only capsaicin.  The chili with the best public relations firm is the Ghost Pepper (Bhut Jolokia) of India. The Ghost is all the rage in culinary spice these days, but it only carries a 1 million SHU warning. I wonder if your mouth can actually feel (not taste) the difference between a Carolina Reaper, a Morgua Scorpion and a Ghost Pepper. I’m not planning to investigate my question.

Habaneros range from 350,000 to 500,000 SHU, depending on the cultivar (Red Savina habaneros were developed to be hotter). Jalapenos manage only a 3500-8000 on Scoville’s scale, and I have a hard time with these!

The Mayans and Incas used chili peppers in war, especially
against the Spanish. The Incas burned chili plants to create a
burning smoke screen, while the Mayans filled gourds with
chili extract and threw them as grenades. In the 2000’s, the
Indian Defense Council considered using Ghost Peppers in
hand grenades as a riot weapon. Everything old is new again.
As little as 10 parts per million (ppm) of capsaicin brings pain to the skin, eyes, mouth or nose. This may be why capsaicin is used as pepper spray weaponry. Pepper spray come in at about 2 million SHU, so some individual Carolina Reapers have more capsaicin than pepper spray. No wonder people vomit when they eat one.

Now for a question with a seemingly easy answer, but one that opens many doors for investigation. Why do we say that spicy foods are “hot?” In culinary terms, “hotness” is made distinct from other spice characteristics by being called piquancy. Chili peppers are piquant (from Middle French for irritating or pricking), not hot. This is where we get the name of picante sauce.

The capsaicin in chili peppers causes pain in the mouth, like a burning sensation. It burns on the skin as well. And eating peppers make you sweat, just like when it is very hot. I'm guessing that this is where the term "hot food" came from. With very spicy peppers, like the reaper or the Morgua Scorpion, the amount of capsaicin brings blistering of the oral mucosa. Basically, your body is sensing a burn, and creates blisters to try and keep the burning compound away from the deeper tissue.

It's true that the closer to the equator people live, the more chili peppers they tend to eat. Believe it or not, eating peppers helps to cool you off. On a very hot day, the heat builds up in your body and you need to get rid of it. Sweating is one way we dissipate heat; the evaporation of water from the skin requires an input of energy, and this comes from the heat of the skin. The loss of heat makes you feel cooler.

We have talked about endorphins in a previous post on exercise and
mood. Pain stimulates the release of endorphins that then block the
transmission of pain signals. It would be nice if you could get the
effect without the pain. Endorphins also impart a sense of elation,
which is one reason chili eaters indulge so often and so heavily.
This is one reason people eat chili peppers. Another reason could be that people like the taste. Chilies do have taste, they aren’t just heat. But I think this a cover for eating them as an endorphin rush. Pain sensation in the body is met with an internal pain-killing cascade that includes the production of endorphins that make a person feel elated and numbs the pain. It’s like the old joke where the guy hits himself in the head with a ball peen hammer because it feels so good when he stops.

So how does eating a pepper turn into a sensation of burning and pain? You definitely transmit neural signals of pain when you are burned by heat, and this is the key. The protein on pain neurons that sense burning heat and conduct the signal to the brain to be perceived as pain – well that same protein is activated by capsaicin! The signal is the same; your brain doesn’t know the difference between activation by capsaicin and activation by scalding heat – it interprets them both as pain!

The protein responsible for this is called TRPV1, and we will have much more to say about this ion channel in the weeks to come. It's a heat sensor, a pain sensor, an acid sensor. It can create pain and inhibit pain. It can cause itch and cough, and maybe prevent cancer. Oh, and it creates vampire bats too.

González-Zamora A, Sierra-Campos E, Luna-Ortega JG, Pérez-Morales R, Rodríguez Ortiz JC, & García-Hernández JL (2013). Characterization of different Capsicum varieties by evaluation of their capsaicinoids content by high performance liquid chromatography, determination of pungency and effect of high temperature. Molecules (Basel, Switzerland), 18 (11), 13471-86 PMID: 24184818

Tewksbury JJ, Reagan KM, Machnicki NJ, Carlo TA, Haak DC, Peñaloza AL, & Levey DJ (2008). Evolutionary ecology of pungency in wild chilies. Proceedings of the National Academy of Sciences of the United States of America, 105 (33), 11808-11 PMID: 18695236

For more information or classroom activities, see:

Scoville heat scale –

Chili fruits –

Fusarium fungus –

Endorphins –