Wednesday, April 9, 2014

Capsaicin – Adding To Or Taking Your Pain

Biology concepts – hyperalgesia, allodynia, analgesia, sensitization, potentiation, desensitization, habituation, burning mouth syndrome

Apparently this is how people shovel snow in the
cold climates. I agree with the form; always bend
with your knees not your back. But the bikini?
Really? I feel like kind of a wimp for talking about
my fingers hurting when I stay out too long.
You know that intense pain you get in your fingers when you've been out in the cold for a while? Why does that happen, and why does it get worse when your hands start to warm up or when you run them under lukewarm or warm water? Believe it or not, the pathways are the same as if you coated them in pepper spray.

Across the USA this winter it was snowy and cold. Where I live we had a record snow fall for December-February, and at least two cold snaps (the Polar Express) that drove wind chills to -25 ˚F or lower.

These conditions gave me ample time to contemplate the issue of hand and finger pain during and after my many shoveling campaigns. I figured it had something to do with exceptions called hyperalgesia (hyper = excess, and gesia = Latin for pain) and allodynia allo = other, and dynia = Greek for pain). It was the burning pain that helped me put it together with chili peppers.

We have talked about how the capsaicin in hot peppers can activate a receptor called TRPV1 that routinely is used by animals to sense noxious (painful) heat and generate a burning pain. Well, there also happen to be some receptors that work the same way for cold. They're called TRPM8 and TRPA1, and we will talk about them in more detail in the posts to come.

The cold sensors may also relay excess cold as pain, but that doesn’t explain why warming up your hands makes them hurt even more. This is requires the explanations of hyperalgesia and allodynia. Hyperalgesia is a perceived pain that is exaggerated beyond what can be accounted for by the stimulus. This does not include your sibling screaming in horror when you flick the lobe of their ear and they go running to mom claiming that you’re trying to kill them. Hyperalgesia is simply too much pain perceived.

Fibromyalgia is a disease that affects women 80-90%
of the time. It is caused by – well, we don’t know.  It
may be secondary to hormone changes, due to CNS
dysregulation, or maybe even stress. Most believe that
it is brought on by a combination of physical and
emotional stressors. This cartoon shows SOME of the
symptoms that can be manifested. Some people have all,
some have only a few, and some have different
symptoms. My complaint is that under skin it says
“various complaints.” Since when does having your
clothes make you feel enormous pain qualify as a
various complaint?
Allodynia is different; this is when your sibling cries out in pain when you're nice to enough to let them have the last donut. In slightly more scientific terms, allodynia is when the body reacts to non-noxious stimuli as if there were noxious. There are basically two types of allodynia, pain brought on by light touch (static mechanical allodynia) and pain brought on by near ambient temperatures (dynamic allodynia).

Tactile (touch) allodynia is rare, it can occur with different kinds of neuropathies, like migraine headaches or a disease called fibromyalgia. Sometimes, even the touch of your clothes on your body can feel very painful, like having a sunburn all over - all the time. In migraines, the pain signals for the headache get mixed up in the central nervous system. This can make even the slightest touch on the face excruciating. And the more often you get migraines, the more likely you are to develop tactile allodynia. Pain is bad, pain when there shouldn’t be any would make me impossible to live with.

In order to explain our cold finger burn when we come inside from the cold out of doors, we need to talk about things like sensitization and potentiation. When one stimulus of a receptor strengthens it response to another stimulus, or when a stimulus to one type of receptor strengthens a stimulus to a second type of receptor – these are examples of sensitization.

On the other hand, if repeated activation of a receptor strengthens each subsequent firing, then this is demonstration of potentiation. Both of these can occur with the heat-sensing receptor TRPV1.

Sometimes capsaicin + TRPV1 makes the TRPV1 react more strongly to heat or more capsaicin. At other times, activation of another TRP, say TRPM8 by cold or TRPA1 by extreme cold or other noxious stimulus, can make TRPV1 activate more strongly to one of its ligands. These are examples of sensitization.

Since the major sensation perceived after TRPV1 activation is pain, sensitization of the TRPV1 by capsaicin or the activation of other TRPs can result in a larger amount of pain when TRPV1 is activated by acid, heat, or even more capsaicin. More pain from these somewhat painful inputs = hyperalgesia.

This cartoon shows the capsaicin/heat ion channel TRPV1
and the noxious cold and chemical pain receptor TRPA1.
Let’s say that you trigger TRPA1 with noxious cold. This lets
in calcium, which activates PKC, This leads to
phosphorylation of TRPA1 (P) which then keeps it open. But
this may phosphorylate TRPV1 too. Now TRPV1 is ripe to be
opened, easier then it normally would be. This is sensitization.
For a real world example, let’s go back to shoveling snow during our cold snap. My fingers got very cold, cold enough to activate the TRPA1 and TRPM8 ion channels. Then when I came inside, anything warm – air, water, a surface, caused much more pain than it should have. This was a result of sensitization of the heat responding TRPV1 channels.

The TRPV1 response was strengthened due to the synergistic response to a different stimulus. The TRPA1 pain receptors are very often expressed on the same neurons as the TRPV1 receptors, so the common pathways can get mixed up as to stimuli. Activation of the cold channels sensitized the heat channels so that warm was now interpreted as very hot – burning hot. It took a 5-10 minutes for pain to subside, but it sure seemed like longer.

In a similar way, but through a slightly different mechanism, TRPV1 signals can get amplified by other TRPV1 agonists. If you get punched in the eye really hard, it hurts. Then it swells up and turns colors. This is inflammation. Inflammatory mediators also activate TRPV1 pain channels. If someone touches your eye now – it hurts a lot more than just touching it before you got punched. This is an example of potentiation. The inflammation signals that activate TRPV1 make it much more excitable and it sends pain signals much more easily.

Another example of this was shown in a 2013 paper. Allyl isothiocyanate (AITC) from wasabi or onions binds can make hot food seem hotter. This applies to both hot meaning spicy, and hot meaning the opposite of cold. Scientists knew that AITC could activate TRPA1 pain sensors, so they thought AITC was sensitizing the TRPV1 through action on TRPA1, but this study showed that AITC can activate TRPV1 directly. Therefore, AITC may make TRPV1 active based on both sensitization and potentiation.

This cartoon tries to illustrate potentiation as different from
sensitization. Potentiation is important learning, you see there
is a higher level of neurotransmitters (dots) in the cleft (space)
after potentiation. Repeated firing strengthens the signal and
makes it easier to fire the neuron because there is more
neurotransmitter and more receptors.
The difference between sensitization and potentiation is in the number of receptors involved. Sensitization means that signaling through one receptor lowers the threshold for a second receptor, while potentiation means repeated signaling through the same receptors will lower its threshold. In both cases, the end result for TRPV1, TRPM8, and TRPA1 is that pains seem exaggerated – hyperalgesia.

What about allodynia – feeling pain when the stimulus shouldn’t be painful at all? TRPV1 and capsaicin can do that as well. This is also seen in my cold finger story. Sometimes, just coming inside and sitting down can make my fingers start hurting more and more. Room temperature shouldn’t cause pain at all; we have said before that TRPV1 is activated by heat only above 43˚C. This would mean that room temperature must be TRPV1-mediated allodynia.

Another 2013 study showed this in another model. Rats with inflammation in one masseter muscle (the big muscles in your cheeks that help you chew) could bring pain on chewing – in the opposite masseter muscle. This was blocked by TRPV1 antagonist, so it was definitely mediated through TRPV1, though they are the TRPV1 receptors in the central nervous system, not those in the muscles. The pain on chewing should have been only on the inflamed side, but it was on the other side too – that’s a form of allodynia.

I was looking for a picture to illustrate burning mouth
syndrome. This is what I found. People pierce their
uvulas?! The gag reflex would be unbearable, and it would
hang down at night and reduce your airway. If burning
mouth syndrome has no known cause, what causes this?
  true central nervous system dysreguation. I think I’d
rather have burning mouth syndrome.
Now for a more unfortunate example of allodynia that seems to involve TRPV1. There is a condition called burning mouth syndrome (BMS). Also known as idiopathic stomatodynia (idio = unknown, pathic = cause disease, stomato = mouth, and dynia = pain). Like the name says, it is a burning, itching, painful mouth disease for which no medical or dental explanation can be found and in which the oral mucosa appears normal. BMS feels like you are chomping on a Carolina Reaper or a Ghost pepper all the time.

BMS can be secondary to some diseases, but not caused by those diseases. It can last for months on end and then just go away, only to return later. There are different types, depending on whether you feel OK in the morning and then it gets worse as the day goes on, or whether it can come and go on a day to day basis.

So why talk about BMS in a story of TRPV1? Well, a 2013 paper shows that people with BMS tend to have more TRPV1 bearing neurons in their mouths. These same patients tended to have more of one type of cannabinoid receptor and less of another in their mouths as well. We know that some endocannabinoids can interact with TRPV1 capsaicin receptors, so it looks like the systems overlap here.  And we also said before that supertasters have more TRPV1 neurons, so they would be more likely to get BMS.

The higher the number of TRPV1 ion channels, the more pain the patients reported, so it really sounds like these pain receptors are involved in BMS.  But they might be the salvation as well.  

Here is an example of a capsaicin spray for reducing
mouth pain. There is also one for nasal congestion. I,
personally, would stay away from that one. These are
based on the idea that some capsaicin can reduce pain in
the mouth – desensitization. And it has been studied in
burning mouth syndrome with some success. We'll
talk a lot more about it next week.
People with BMS often report that the pain is reduced when they eat, so perhaps gustatory sensing can overwhelm the pain sensing. And maybe chili peppers will lead the way. A 2012 study indicated that a capsaicin rinse (0.02% capsaicin) reduced the pain of BMS. It decreased the pain for most patients, but didn’t get rid of it for any of them. Ironically, they complained that it burned their mouths – as if they don’t feel that all the time.

An earlier review also showed that some studies showed a decrease in BMS symptoms via a topical capsaicin preparation. They just didn’t like the taste. This opens up a whole new bunch of questions. How can you use capsaicin to relieve burning pain? It causes burning pain!!

You use pain to stop pain – huh? You ponder that for a week.

Borsani E, Majorana A, Cocchi MA, Conti G, Bonadeo S, Padovani A, Lauria G, Bardellini E, Rezzani R, & Rodella LF (2013). Epithelial expression of vanilloid and cannabinoid receptors: a potential role in burning mouth syndrome pathogenesis. Histology and histopathology PMID: 24190005

Silvestre FJ, Silvestre-Rangil J, Tamarit-Santafé C, & Bautista D (2012). Application of a capsaicin rinse in the treatment of burning mouth syndrome. Medicina oral, patologia oral y cirugia bucal, 17 (1) PMID: 21743415

Alpizar YA, Boonen B, Gees M, Sanchez A, Nilius B, Voets T, & Talavera K (2014). Allyl isothiocyanate sensitizes TRPV1 to heat stimulation. Pflugers Archiv : European journal of physiology, 466 (3), 507-15 PMID: 23955021

Simonic-Kocijan S, Zhao X, Liu W, Wu Y, Uhac I, & Wang K (2013). TRPV1 channel-mediated bilateral allodynia induced by unilateral masseter muscle inflammation in rats. Molecular pain, 9 PMID: 24377488

For more information or classroom activities, see:

I looked for good websites on sensitization and potentiation, but none are very good at explaining them in this situation, most are for learning pathways.

Pain from warm after cold –

Fibromyalgia –

Burning mouth syndrome -

Wednesday, April 2, 2014

It’s Not Just Chili Peppers That Are Hot

Biology concepts – cinnamaldehyde, nasal hyperreactivity, piperine, allyl isothiocyanate, eugenol, gingerol, tinyatoxin, osmotic stress, agonist/antagonist

The last few years have seen the rise and fall of The Cinnamon Challenge. I can’t tell you why it came, but I can explain why it went. And the reason relates to the capsaicin receptors we have been talking about.

Don’t think cinnamon candy can be hot. Your unbearably hot
cinnamon bears from Jelly Belly and your Atomic Fireballs are
both flavored with cinnamon oil. Fireballs have been around
since the 1950’s which explains the atomic reference. It takes
over two weeks to make one. Cinnamon is not ranked on the
Scoville scale because the main spicy compound is
cinnamaldehyde, not capsaicin. But there is some capsaicin in
cinnamon oil, so I think it could be ranked without breaking
some long standing policy.
The challenge goes like this: you take one tablespoon of cinnamon and try to swallow it all in 60 seconds without any water. If any one tells you they did it and came out O.K., they’re lying. If you see video of someone doing it easily, it's been faked.

Here’s how the challenge works for everyone. The compounds in cinnamon stimulate a coughing reflex (explained below). When you cough, you expel air and you have a compulsion to inhale. Here’s where the trouble starts. The inhalation carries a good portion of the cinnamon powder down your trachea and into your lungs.

Now you’ve done it. The ensuing coughing fit can be powerful enough to break ribs. The compounds in the cinnamon immediately begin to burn your lungs, make your eyes water, make your nose run, and increase your breathing rate. More inhalations carry more cinnamon into your lungs and the burn intensifies. YOU WILL blow it out, spit it out, vomit it out. The pain in your lungs will likely last for three weeks or more. Sounds like fun, doesn’t it?

Here’s the biology of the why it ends well for no one. Cinnamon contains compounds called cinnamaldehyde and eugenol, as well as capsaicin (much lower amount). The capsaicin and eugenol activate TRPV1 ion channels. Cinnamaldehyde is a different class of molecule from the capsainoids, so it does not activate TRPV1, but it does activate a powerful member of another subfamily, TRPA1. We will talk more about this receptor in later posts.

TRPV1 is involved in cough reflex, runny nose, and in the burn that the follows the challenge. The TRPA1 activation causes powerful pain in the lungs and trachea. Together, these compounds result in the involuntary cough, reflexive inhalation of cinnamon into the lungs, and all the pain that follows from activating the TRPV1 pain receptors in your lungs. Now you know WHY you should avoid the challenge.

Asthma is a trigger for airway or nasal hyper-reactivity.
It is easy to see how this could get out of hand, especially
when it can lead to chronic inflammation and damage of
the airway tissues. And to think, it is mediated in part by
the same receptor that makes your Sunday afternoon
chili stew spicy.
Don’t laugh at the portion of the response that takes place in your nose. My mother-in-law got some chili pepper oil up her nose once, and she still refuses to be in the same room as a chili. Her runny nose, sneezing, and watery eyes were directly due to the capsaicin. But for some people it happens for no reason. This is called nasal hyper-reactivity.

In some cases the exaggerated nasal response is due to an allergen, but in other people the trigger is unknown. The TRPV1 ion channels in the nasal mucosa may be over-expressed (too many of them). Their activation brings mucous, bronchoconstriction, cough, and sneeze.

The evolutionary strategy here is like with the cinnamon. Your body is trying to keep toxic or harmful substances out of your lungs. A new study has linked nasal hyper-reactivity to TRPV1 action alone, without need of other receptors. What is more, the paper identifies a new TRPV1 antagonist. An antagonist is a molecule that binds to the receptor but does not activate it, and it can prevent the receptor’s stimulation by molecules that would normally activate it (agonists).

This new antagonist of TRPV1 can suppress the nasal hyper-reactivity and give some relief those afflicted. You may think nasal hyper-responsiveness is trivial, but it’s snot – get it? It’s snot.

Nasal hyper-reactivity is often diagnosed by assessing an exaggerated response to capsaicin in the nose. I can’t imagine how any response to nasal capsaicin could be considered exaggerated. It’s just lucky for us that capsaicin isn’t volatile. Less of it gets into the air because it has a long hydrocarbon tail. 

Because it isn’t volatile, capsaicin doesn’t have an odor, not until you chew it and volatilize it yourself into your nose do you know you’re in trouble. The runny nose is your body recognizing there is something there that you really don’t want in your lungs. It’s bad enough with cinnamon, can you imagine getting capsaicin in your lungs?

The capsinoids are a group of compounds within the
vanilloids. You can see the resemblance to vanillin, so
there are all vanilloids. The different capsinoids are all
found in chili peppers, but capsaicin is the most
abundant and potent, but the structures of the different
capsinoids are very similar.
Pure capsaicin ranks at 16 million Scoville heat units (SHU). But it isn’t the  only capsinoid in chili peppers. There is also dihydrocapsaicin (15 million SHU), nordihydrocapsaicin (9.1 million SHU), homocapsaicin (8.6 million SHU), and homodihydrocapsaicin (8.6 million SHU). Each of these can activate TRPV1 to bring the burn. But it doesn’t stop there; many other compounds can bind to TRPV1 as well. Here's some of them:

Piperine (100,000 SHU) is the spicy compound in black and white peppercorns. You already know black pepper is spicy, and it activates TRPV1 just like capsaicin. Remarkably, it's even more efficient than capsaicin at opening the TRPV1 ion channel. However, it's found in lower amounts that capsaicin in most chilies and has a greater ability to desensitize TRPV1, so it burns less. We will talk about desensitization of TRPV1 in the coming weeks.

Allicin is found in garlic and onions; they can burn too. Raw garlic is especially pungent; try it some time. Garlic is used in many folk medicines – it has been show to prevent or treat fungal infections, lowers blood pressure, is neuroprotective, and can slow the growth of some cancer cells. Some of these effects are mediated by TRPV1. Oh, and it wards off vampires too.

Eugenol is found in many foods, including cinnamon, bay leaf, clove, and allspice. It activates TRPV1, but like piperine, it can be desensitizing too. For this reason, eugenol has a numbing effect and is often used in dental preparations. If you have ever had a cavity filled with the silver amalgam, you probably smelled cloves in the process - that was the eugenol. Just recently it has been shown that eugenol also activates TRPA1 pain receptor, so maybe the dentists should be rethinking their strategy.

Radishes, horseradish, wasabi, and mustard contain allyl isothiocyanate (AITC). This compound binds to both TRPV1 and TRPA1, so they can generate a lot of pain, and the heat sensation as well. In mustard seeds, the AITC isn’t produced until the seeds are broken and an enzyme is released that converts one compound into AITC. This is why stone ground mustards with larger chunks of seeds are less spicy.

In the horse trade, a raised tail means a younger, livelier
horse. When someone wanted to sell an old, worn out
horse, but get more money, they might put a piece of
ginger in the anus of the horse. The burn from the
gingerol would make it raise it’s tail. It has also been
used in horse shows, but is now illegal. Oh yes,
sometimes “gingering a horse” also involved live eels.
The spicy compound is not stored in the plant as AITC because it's harmful to the plant as well. Only when an herbivorous predator comes along and starts munching on the plant is the toxic chemical produced. A new study (2013) shows that AITC actually makes TRPV1 more sensitive to heat, so using wasabi with hot food will really crank up the pain.

Ginger contains gingerol (60,000 SHU), but when you cook it gingerol is converted to the sweeter and more aromatic form called zingerone. Both can activate TRPV1.  There is also gingerol in mustard oil, so both mustard and ginger have been used in folk medicine, like plasters they use to slather on wounds. For a less appropriate use of ginger, see the photograph at the right.

Camphor is used in things like Vicks VapoRub. It activates TRPV1, so you feel warm, but it can also activate a cool receptor, so it seems to open up your nose. We will have much more to say about this in a couple of weeks. Found in certain trees, camphor is slightly analgesic (pain killing), and is antimicrobial, so it does serve a purpose in Vicks.

In addition to these plant-based agonists, TRPV1 is activated by other things as well. We already talked about how the channel is opened by acid (excess protons), but it can be activated by inflammation in tissues and some endogenous pain killers as well, like the endocannabinoids we talked about at New Year’s.

Tinyatoxin (and resiniferatoxin for that matter) are
produce by the Euhorpbia poissonii plant. Native to Nigeria,
its extract is used by natives as a pesticide. The tinyatoxin
and resiniferatoxin are neurotoxic and can kill TRPV1-
expressing neurons, so they are being looked at as a
way to treat chronic pain.
There are artificially produced agonists as well. Resinferitoxin activates the heat receptor TRPV1. It rates 108.8 billion on the Scoville scale! Scientists are trying to find a use for it in chronic pain and other diseases (more in two weeks). There is also tinyatoxin from the Euphorbia plant. It is slightly less spicy, about 5.3 billion SHU. It is a neurotoxin and can kill you in large amounts.

One last agonist for TRPV1 – osmotic stress. This refers to the movement of water out of cells (so they shrink) or into cells (so they swell) when there is an imbalance of salts inside and outside of the cell. Too much salt in the extracellular fluid is called hypertonic, and water will flow out of cells and toward the more concentrated salts. Too little salt in the extracellular fluid is called hypotonic and water will move into the cells where the salt concentration is higher.  We want an isotonic environment, where the slat is the same in and out of the cell.

TRPV1 sense osmotic changes, specifically hypertonicity. A 2010 paper shows that there is a TRPV1 in the brain that does not react to heat or capsaicin, but does respond to osmotic stress. TRPV1 sense cell shrinkage and signals the hypothalamus of the brain to release a hormone called vasopressin (also called ADH). This hormone causes more water to be retained and more salt to be excreted, This lowers the salt concentration outside the cells and the cell shrinkage can be corrected.

Osmotic pressure is related to the amount of water versus the
amount of salts in the water. In the cartoon, the salts are
represented by the blue spheres. Water will travel to wherever
salts are highest, because that means water concentration is
lower. Hypertonic means water will flow out of cells, while
hypotonic means water will swell the cells, even to the point of
lysing them. The representative cell is a red blood cell, since
they are very susceptible to osmotic changes.

Another receptor of the same subfamily, TRPV4, senses swelling during hypotonic crises. This then triggers the hypothalamus to release less vasopressin and the salt concentration will increase outside the cell; excess fluid in the cell will flow out of the swollen cells. A 2011 paper shows that TRPV1 works only on shrunken cells and TRPV4 only on swollen cells.

Using TRPV1 in osmoregulation makes sense. It is closely related to thermoregulation, considering how you use sweating to get rid of excess heat. Sweating messes with osmotic pressures. Nature is smart that way.

Next week, more functions of TRPV1 – it can make pain worse and stop pain. How can that be?

Holland C, van Drunen C, Denyer J, Smart K, Segboer C, Terreehorst I, Newlands A, Beerahee M, Fokkens W, & Tsitoura DC (2013). Inhibition of capsaicin-driven nasal hyper-reactivity by SB-705498, a TRPV1 antagonist. British journal of clinical pharmacology PMID: 23909699

Chung G, Im ST, Kim YH, Jung SJ, Rhyu MR, & Oh SB (2014). Activation of transient receptor potential ankyrin 1 by eugenol. Neuroscience, 261, 153-60 PMID: 24384226

Alpizar YA, Boonen B, Gees M, Sanchez A, Nilius B, Voets T, & Talavera K (2014). Allyl isothiocyanate sensitizes TRPV1 to heat stimulation. Pflugers Archiv : European journal of physiology, 466 (3), 507-15 PMID: 23955021

Ciura S, Liedtke W, & Bourque CW (2011). Hypertonicity sensing in organum vasculosum lamina terminalis neurons: a mechanical process involving TRPV1 but not TRPV4. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (41), 14669-76 PMID: 21994383

Sudbury JR, Ciura S, Sharif-Naeini R, & Bourque CW (2010). Osmotic and thermal control of magnocellular neurosecretory neurons--role of an N-terminal variant of trpv1. The European journal of neuroscience, 32 (12), 2022-30 PMID: 21143657

For more information or classroom activities, see:

Agonist/antagonist –

Eugenol –
Gingerol –

camphor -

tonicity –

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 -