Wednesday, April 23, 2014

Chili Peppers Run Hot And Cold

Biology concepts – obesity, brown adipose tissue, agonist/antagonist, protective hypothermia, hyperthermia, reactive oxygen species, ischemia, hypoxia

When The Wizard of Oz was released in 1939, it just barely turned a profit. The '39 version was the third attempt at filming the children’s classic, and the first two efforts had not fared much better.

I don’t see how people didn’t take to the Wizard of Oz right away.
It had new technology for the movies, a good villain, and all those
little people. The tin man on the left was played by Jack Haley, but
originally it was supposed to Buddy Ebsen (Jed from the Beverly
Hillbillies). Unfortunately, the lead metal in the makeup almost
killed him during the makeup/costume tests. Glenda the good witch
(Billie Burke) had that squeaky voice. She only began acting
after her husband, Flo Ziegfeld, Jr. (son of the Ziegfeld Follies
creator), went belly up on Black Monday in 1929.
Over time, what was first considered bad has become a classic. In what many people consider the best year ever in film, The Wizard of Oz is now a favorite among favorites, more than Goodbye Mr. Chips, Mr. Smith Goes to Washington, Stagecoach, or even Gone With the Wind – all produced in 1939.

It’s smart to hang on to useless things and knowledge, something might change. For Oz – it was television. For some reason, this film translated better to TV than it did the big screen. The Library of Congress now rates it as the most viewed film ever. And it wasn’t even shown on TV until 1956. The weird part – very few people in 1956 owned a color television, so Dorothy’s entrance into the land of Oz was no big deal for most folks until the late 1960’s.

Why am I telling you this story? Because the same thing happens in biology and medicine. Problems can become assets if the right environment is created or the proper setting is found. We've been discussing the capsaicin receptor, TRPV1, for some weeks, and this is where I find a negative being turned into a positive.

As you know, the TRPV1 capsaicin receptor is primarily a heat sensing receptor for thermoregulation of the body. If activated by noxious (painful) high temperatures, it generates a pain signal and initiates a cooling program for the body, including sweating.

In an effort to block TRPV1 to create analgesia (no pain), the problem has been that blockers also stop thermoregulation and the patient overheats. This prevents most TRPV1 antagonists (substances that bind the receptor but don’t allow function) from being used as analgesics. But what about in other situations?

I was wondering if TRPV1 antagonists might be helpful in obesity, by helping burn off some fat through increased cooling activity. If they are indeed helpful, nobody knows about it yet. I couldn’t find even one paper that studied TRPV1 antagonists as a way to induce increased energy expenditure and weight loss. In fact, I learned just the opposite. Capsaicin and other TRPV1 agonists might help with weight loss.

On the left is brown fat and white fat. You can see that brown fat
actually looks browner because of all the mitochondria that it
contains. White fat contains a lot more lipid. The right cartoon
shows that a cold challenge initiates uncoupled fat metabolism in
brown fat, creating heat. But the cold also releases more fatty acids
from white fat, which can then be burned by the brown fat. The
involvement of bone comes from bone breakdown. Breakdown
releases a protein that stimulate white fat to release fatty acids,
this would provide energy for the brown fat.
We have discussed how TRPV1 activation by noxious heat helps to cool the body, but it turns out that noxious cold leads to TRPV1 activation as well, but in these cases, it brings an increase in heat production. So TRPV1 can cool you down or warm you up as needed. Pretty cool. You'll have to wait a few weeks to find out how a heat receptor senses noxious cold.

The heat induced by cold comes from increased activity of brown adipse tissue (BAT) – brown fat. We have talked about BAT before, how it is especially important for infants because they lose heat so easily. Brown fat has lots of mitochondria, but they don’t make ATP. They convert all the energy they burn into heat.

New research is showing that BAT can be important to adults as well. Those people that have more BAT tend to have less white fat, the kind that makes you bigger. What is more, a 2013 paper shows that cold temperature exposure can help create more BAT, and this effect is mimicked by capsaicin and other TRPV1 agonists.

If you expose adults to mildly cold temperatures for six hours a day, they start to make more BAT and this means they burn more energy for heat; therefore less energy is left to be stored as white fat. But the study also showed that giving the people capsaicin for weeks in a row generated the same increase in BAT and stopped white fat accumulation.

One mechanism involved is that TRPV1 agonists stimulate an increase in uncoupling protein (UCP) expression in BAT. This is the protein that permits the BAT mitochondria to produce lots of heat instead of lots of ATP and a little heat. The uncoupling protein activity in BAT uses excess calories to produce heat, so those calories are not available to make fat.

Here is how a stem cell becomes a fat cell (adipocyte).
The mesenchymal cell can go two directions, one
toward fat and one toward muscle. But notice you can
get to a brown fat cell through the pathway meant for
muscle cells. PG stands for prostaglandins; different
profiles of prostaglandins lead to a decision to become
a brown fat cell or a white fat cell. We know this picture
is incomplete now, because we have evidence that
TRPV1 agonists can drive the decision between
brown fat and white fat.
But there may also be another mechanism at work. A 2014 study in laboratory petri dishes shows that cells destined to become white fat cells can be stopped from changing by capsaicin. In cells called preadipocytes, capsaicin stopped their proliferation (dividing to become more cells) and their differentiation (changing) to become full-fledged adipocytes (fat cells). Another study (2012) showed that in liver, capsaicin could prevent the accumulation of white fat build up (called fatty liver) and could actually induce UCP protein expression in some fat cells, turning them into liver BAT. Amazing.

This all sounds fine, but the proof is in the pudding, so to speak. Capsaicin and other TRPV1 agonists have been shown to reduce white fat and total body mass in rabbits fed a high-fat/1% capsaicin diet, in mice fed a high sucrose diet, and in human patients kept cold or fed hotTomorrow I’m going to start eating hot peppers in a cold house – I’ll shrink away before your eyes.

What about on the other end of the thermometer? People freeze to death when they get too cold, and TRPV1 agonists will cool you off when too warm. No TRPV1 activity causes a reactive hyperthermia, and too much TRPV1 activity will induce a reactive hypothermia. But is there a time when inducing cold in a body with capsaicin would be a good thing?

Would we be talking about it if there weren’t an exception? It's called protective hypothermia, and it has become a very important treatment adjunct during stroke and some over conditions.

Ischemia (left) is often associated with coronary (heart) arteries.
Ischemia means a reduction in blood flow to a tissue or the whole
body. With less blood flow comes less oxygen, so tissue cells suffer.
Several mechanisms can lead to a lessening of blood flow. On the
right is hypoxia, which is often used when referring to the brain or
specific organs. Hypoxia is a reduction in oxygen to the tissues,
whether it comes from a reduction in blood flow or some other
reason, like fewer red blood cells, lower oxygen in the air, etc.
Protective hypothermia is an induced cold that is used to protect tissues from post-ischemic injury. When there is a reduction in blood (ischemia) or oxygen (hypoxia) to a tissue or organ, the cells are starved for oxygen and then become starved for ATP (you need oxygen to make ATP). With lower oxygen over time, either from low oxygen or reduced blood flow, the tissues get used to having lower oxygen levels.

Getting used to it would include down-regulating the systems that would normally combat the damage that could be caused by reactive oxygen species (ROS). Whenever oxygen is being used in tissues, ROS are an unfortunate by-product. Their name tells you that they’re reactive, which means they can react with many molecules in the cell and they will do significant damage.

When normal blood flow or oxygen perfusion is re-established, the sudden increase in O2 causes a spike in ROS (reperfusion injury) – until the cell can ramp up its antioxidant capabilities again. What medicine needs to do is find a way to increase the O2 without increasing the ROS damage.

Cold seems to do the trick. Reducing the temperature of the body reduces cell death and ROS after cardiac arrest, stroke, neonatal encephalopathy, or traumatic spinal/brain injury. Why? There have been a few ideas why.

The old hypothesis was that the lower temperature would reduce cellular metabolism, so that there is less need for O2. This would imply that the lower the temperature, the better. But very low temperatures might lead to injury or damage on their own. Also, extended cold could bring pneumonia or promote sepsis. Maybe colder isn’t always better.

There are many ways to get a perfusion injury when
oxygenation of the tissues is reestablished after hypoxia.
We talked about the free radicals (ROS) in the post. The
other injuries are a bit less obvious. We mentioned the
problems with membranes and the increase in apoptosis. 
The other two are related to spasm of the muscle cells in
the vessels which would again reduce oxygen levels, and
a nonspecific activation of coagulation and cell killing that
would lead to damage as well.
Now scientists think protective hypothermia works in a couple of different ways. Colder temperatures bring a neuroprotective effect by preventing apoptosis (programmed cell death). Less O2 means less ATP being made, and a decrease in ATP usually means that the mechanisms for maintaining proper ion movements in and out of the cell are hampered. Increased ion flux triggers apoptosis. So lower temperature brings less ion flux, less damage, and less cellular suicide.

Even a small decrease in temperature can stabilize the cell membrane independent of ATP levels. This makes sense; membranes are mostly lipid, and lower temperatures make fats stiffer – like cold butter. This will decrease ion movement across the membrane and reduce cell damage.

Lastly, decreased body temperature brings less reperfusion injury. In this case, maybe the old hypothesis was correct. Colder tissues metabolize less, so less oxygen will be needed and less ROS will be produced.

So cold is helpful, but how do you do it? You can lower the body temperature by using cooled IV fluid, cold mist in the nose, or even wrapping specific body parts in cooled blankets. But perhaps TRPV1 agonists could help cool the body from the inside.

As of early 2014, the evidence for TRPV1 agonists is only in mouse models, but it’s looking good. A study in 2011 showed the an injection of capsaicin into the abdominal cavity three hours before inducing hypoxia reduced the volume of dead tissue and the amount of apoptosis in the brains of the mice.

This is the fruit of the Evodia rutaecarpa Bentham plant. It has been
used in Chinese herbal medicine for hundreds of years. We are
starting to learn why it does what it does. It has been shown to be
an anti-cancer, anti-obesity, anti-vomiting, anti-hypertension
anti-ulcer, anti-pain drug. Five thousand years of
culture leads to good drugs like this.
Two 2013 studies added strength to the 2012 study. One experiment used a Chinese herbal medicine that contained a chemical called evodiamine. It had been known that evodiamine helped in stroke victims, but we didn’t know why. Evodiamine was shown to be a TRPV1 agonist in 2012, and the 2013 study showed that after a stroke, the agonist increased cell survival mechanisms and reduced apoptosis.

The other study from 2013 showed that capsaicin also helps in reperfusion injury. Mice were given strokes by blocking an artery in the brain and then unblocking it to replenish the blood and oxygen. Injecting capsaicin within 90 minutes of the re-establishment of blood flow produced a mild hypothermia, reduced the volume of dead tissue in the brain, and increased neural function. This didn’t occur in mice without TRPV1, so we know the capsaicin receptor was responsible. Sounds like emergency rooms are going to start stocking hot peppers.

Today we discussed interesting uses for capsaicin and its receptor in temperature-related functions. Next week, some weird functions for TRPV1 that have little or nothing to do with temperature.

Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, & Saito M (2013). Recruited brown adipose tissue as an antiobesity agent in humans. The Journal of clinical investigation, 123 (8), 3404-8 PMID: 23867622

Feng Z, Hai-Ning Y, Xiao-Man C, Zun-Chen W, Sheng-Rong S, & Das UN (2014). Effect of yellow capsicum extract on proliferation and differentiation of 3T3-L1 preadipocytes. Nutrition (Burbank, Los Angeles County, Calif.), 30 (3), 319-25 PMID: 24296036

Yoneshiro T, & Saito M (2013). Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management. Current opinion in clinical nutrition and metabolic care, 16 (6), 625-31 PMID: 24100669

Muzzi M, Felici R, Cavone L, Gerace E, Minassi A, Appendino G, Moroni F, & Chiarugi A (2012). Ischemic neuroprotection by TRPV1 receptor-induced hypothermia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 32 (6), 978-82 PMID: 22434066

Cao Z, Balasubramanian A, & Marrelli SP (2014). Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion. American journal of physiology. Regulatory, integrative and comparative physiology, 306 (2) PMID: 24305062

For more information or classroom activities, see:

Brown adipose tissue –

Protective hypothermia -

Wednesday, April 16, 2014

Using Pain To Stop Pain

Biology concepts – desensitization, habituation, counter irritation, cautery, heat sensing, pain, chronic, acute, analgesia

Gout usually attacks middle-aged men and the big toe
joint is a favorite spot. But it can occur anywhere and
in anyone. The accretions or urates build up and clog
the joint, causng poor function and intense pain,
painful enough that even the weight of a sheet on it at
night is too much. Usually the acute attacks are far
worse, and become less painful gouty arthritis
as they become chronic.
Sometimes people use pain to combat pain, as silly as it may sound. Gout is an arthritis-like disease where uric acid crystals (a waste product from many different pathways, especially purine nucleotide metabolism) buildup in the joints and can cause life-altering pain.

Before adequate drugs and diet suggestions came along to help to rid the body of excess urates, people were sometimes left to to their own devices in trying to relieve the pain of gout. One home remedy was described in a history text from the 500’s CE called Historium Libri Decem.

In the book, the Bishop of Cahors had gout so bad that he would stick a fireplace poker in the embers and then apply it to his foot and shin. Man oh man, it must be some major discomfort if cauterizing your toes and foot becomes a good idea.

The practice of cautery (from Greek for branding iron) for gout lasted for hundreds of years, with a 17th century century surgeon from France pronouncing that he didn’t really believe in external remedies for gout, except of course, for cautery with a red hot poker.

The above example falls under the heading of analgesia (an = not, and gesia = pain) by counter irritation. Counter irritants basically substitute one pain for another.  You have two competing stimuli, both of which create pain. One is probably chronic (long-term, comes from chronus = time); this is pain from which the person wants relief.

The second pain is acute (from Greek for sharp). The second pain is geared toward relieving the first pain. Who hasn’t bitten a knuckle or lip while getting an injection or experiencing some other pain? Is it just a distraction, a placebo, or is there biology at work?

The concept of counter-irritation is old. Before we had any idea how it worked or even if it worked, counter irritant uses approached the bizarre. Heart attack and angina pectoris (pain from partially blocked cardiac vessels) often shoot a pain down the left arm. So early physicians decided that if counter irritants were placed on the left arm, they could short circuit the pain as it was sent out but before it could come back to the heart.

Cupping is one example of a counter irritant to relieve pain. The
little pins on the tops of the cups are for drawing a vacuum. Dry
cupping is shown on the left, no blood is drawn. Wet cuppin is
on the right, where more vacuum is used and blood is suck out
of the skin through the pores. Believe it or not,
wet cupping is more common.
Counter irritants these days are sometimes just as odd. For example, blistering horse legs to help their knees goes against common sense. There is also something called cupping, which is Chinese in origin. Suction is created in cups that then are placed on the skin. The skin is drawn up into the cup, and blood is drawn to the surface.

Originally used to promote healing, cups are used to quell pain too. As far as truly scientific studies, the only thing we know about cupping and pain relief is that the studies have been poorly conducted – better studies are needed. But never underestimate the power of the placebo. If a patient thinks it works, then it works.

Other types of counter irritants include scarification – scratching until the epidermis is removed. Many people with chronic itch practice this everyday of their lives. Chemical irritants that act on the skin are called rubefacients because they turn the skin red (through dilation of blood vessels underneath). Capsaicin, menthol, camphor, methylsalicylate (more on this below), eucalyptus oil, all have been tried as rubefacient counter-irritants.

This youngster suffers from Alagille syndrome.
It causes bile to stockpile in his liver which
makes him itch all over, all the time. He wears a
special suit to prevent him from scratching until he
bleeds. The scratching is a type of counter irritant
and will will talk more about itch and capsaicin in a
couple of weeks. The young boy is on the
liver transplant list.
Often, the counter-irritant is applied at the same place where the deep pain is, because the users believe it must act on the set of nerves that sense the pain in both areas. Capsaicin rubs, or things like BenGay (methyl salicylate) are rubbed on the skin where the muscles or joints ache. But this may not be the way that they act.

A study from 2009 showed you could counter a long-standing pain in the right leg by immersing your left foot in cold water. Painfully cold water activates TRPM8 and TRPA1. Doing this only to the left foot reduced shock pain in the right leg by 50%. Apparently it acts to confuse pain signals at the level of the spinal column.

So just how does counter irritation relieve pain? There are competing ideas. Perhaps the acute pain of the irritant sparks a release of endorphins (opiate pain killer made by our own body). This seems plausible, but chronic pain patients have very high levels of endorphins in their blood; they just seem to not respond to them.

The hypothesis of a nerve overload is less precise, and may actually reflect other mechanisms at work. Overload in general would mean that a huge amount of neural input at the same time overloads the spinal nerves at that point and results in no signals getting through. This may be how the left foot right leg example works.

Even if some of these mechanisms contribute to counterirritant action, additional processes are probably at work as well, namely desensitization and habituation. You’ll be surprised how much TRPV1 heat/capsaicin sensors are involved. Capsaicin causes pain because your body interprets it as noxious heat (TRPV1), but somehow, you can also use capsaicin to take away pain.

I have used the joke before, but it keeps working. Hitting
yourself with a hammer over and over could desensitize
pain receptors, induce endorphin release, distract from
other pain, confuse spinal signaling – all of which are
plausible mechanisms for counter irritation.
The truth is what makes it funny.

In simple terms, desensitization of the TRPV1 channels means that while some activation causes pain, continued activation depletes the neuron of the molecules need to create or transmit the signal, and the pain neuron can’t fire any longer. If it can’t fire, there’s no pain – analgesia.

There are two kinds of desensitization, homologous means that continued use of one agonist on a receptor makes that receptor less able to respond to that agonist. Heterologous desensitization is when other agonists work on receptors in another part of the tissue. 

The heterologous type of desensitization sounds an awful lot like the example above where really cold water on one foot reduces pain in the other foot. So this could be one of the mechanisms of counter irritants.

On the other hand, consider the old example of placing a frog in hot water (video here) – it jumps out due to TRPV1 heat/pain signaling. But if you place a frog in warm water and then heat it slowly, the frog won’t jump out. It will sit there until it’s a frog leg dinner. This is habituation (tolerance) and perhaps homologous desensitization as well. Perhaps capsaicin pain creams act by habituation and counter irritation, nothing says they can’t do both.

Another desensitization/habituation model uses resiniferatoxin injected into the covering of the brain (epidura) to stop neuropathic pain. Remember that resinferitoxin is a strong capsaicin-like molecule, with a score of 108.8 billion Scoville units. It is such a strong agonist that it alone can desensitize TRPV1 in short order - so much that it is termed an anti-nociceptive agonist.

Even more amazing, a Sept. 2012 study used two agonists of TRPV1, capsaicin and MRS1477. Use one or the other and you get hyperalgesia. But administer both at the same time and you get analgesia. In this case, they are hoping that this will be an alternative to opiates in cancer-mediated pain.

This all sounds great – TRPV1 is on small (C type) and some larger (Adelta) pain fibers, and wearing them out can reduce pain. But wouldn’t it just be easier to block them with an antagonist (something that binds but doesn’t activate)? Well, there’s a problem with that – TRPV1 does more than just signal pain.

If you block TRPV1 activity to produce analgesia, you also block its heat-sensing role. Now your body won’t know when it is getting hotter and won’t cool itself down. You end up with hyperthermia and that can kill you. This has been a consistent problem with TRPV1 agonists as analgesics, including if resinferitoxin is given orally – but who would want 108.8 billion SHU in their mouth?

It is the oral TRPV1 antagonists that seem to bring the hyperthermia when trying to treat osteoarthritis. The hyperthermia has been attributed to the action of TRPV1 antagonists in the GI tract. New work shows that activity of TRPV1 is increased (and the expression) in the joint during osteoarthritis, but no increase in expression or activity in the spinal column. Injection of a TRPV1 antagonist into the joint to stop the pain signals from the joint without the hyperthermia.

Wint-O-Green Life Savers are famous for emiting light
when chewed. This is called triboluminescence and also
occurs when you rub quartz together or pull tape from
a roll. The mechanism is through energy release by
mechanical breaking of crystals or bonds. In the case
of life savers, sugar dried to crystal will undergo
triboluminescence, but the light is often in the UV
range. But the oil of wintergreen chemistry converts
the UV to visible light. And now you know.
But there's hope for oral TRPV1 antagonists. New polypeptides called APHC1 and APHC3 show analgesic activity in vivo at reasonable doses (0.01-0.1 mg/kg) by blocking capsaicin, heat, and acid activation and did not cause hyperthermia. They can be used IV or perhaps orally, they don’t need to be injected into a specific joint or into the spinal column.

Some chemicals may be both agonistic and antagonistic for TRPV1. A new paper states that methyl salicylate (oil of wintergreen) activates TRPV1, so it induces a warm feeling, but it also blocks TRPV1 activation by capsaicin, acid, anandamide, and perhaps inflammatory mediators. This means that it can be analgesic, which is why it's the main ingredient in BenGay.

However, the same paper indicates that analgesic activity of methyl salicylate might be due to its TRPV1-independent activity on a different system, the same pain generating system blocked by aspirin (cyclooxygenase). Arguing against this - BenGay is amazingly painful when loaded into a teammate’s underwear or jock. Take my word for it.

Acupuncture is a source of constant argument in science.
Does it really do something or is it all placebo. Recent
(2012-2014) papers are starting to show that it does have
specific physiologic actions. Here is shown the
electroacupuncture. In medical terms, this is equivalent to
TENS (transcutaneous electrical nerve stimulation). In TENS,
the current is passed through the area that is being
affected, but in acupuncture, a remote area may be used,
according to acupuncture charts.
On a completely different front, a 2012 study of electroacupuncture showed that it could reduce the size and frequency of the action potentials from TRPV1 nociceptive neurons.  To determine how this might work, the same acupuncture point (st36) was shown in a 2014 paper to block pain by stimulating a pain pathway. If you block the anti-nociceptive TRPV1 channels with 1% capsaicin, then the acupuncture won’t stop the pain. Once again, TRPV1 works in both pain and anti-pain. That’s a confusing exception.

Next week, capsaicin receptors are also used in some other systems, not just heat and pain. Who would have guessed that eating chili peppers could stop but also cause cancer?

Andreev YA, Kozlov SA, Korolkova YV, Dyachenko IA, Bondarenko DA, Skobtsov DI, Murashev AN, Kotova PD, Rogachevskaja OA, Kabanova NV, Kolesnikov SS, & Grishin EV (2013). Polypeptide modulators of TRPV1 produce analgesia without hyperthermia. Marine drugs, 11 (12), 5100-15 PMID: 24351908

Tobaldini G, de Siqueira BA, Lima MM, Tambeli CH, & Fischer L (2014). Ascending nociceptive control contributes to the anti-nociceptive effect of acupuncture in a rat model of acute pain. The journal of pain : official journal of the American Pain Society PMID: 24412800

Lee MG, Huh BK, Choi SS, Lee DK, Lim BG, & Lee M (2012). The effect of epidural resiniferatoxin in the neuropathic pain rat model. Pain physician, 15 (4), 287-96 PMID: 22828682

Kelly S, Chapman RJ, Woodhams S, Sagar DR, Turner J, Burston JJ, Bullock C, Paton K, Huang J, Wong A, McWilliams DF, Okine BN, Barrett DA, Hathway GJ, Walsh DA, & Chapman V (2013). Increased function of pronociceptive TRPV1 at the level of the joint in a rat model of osteoarthritis pain. Annals of the rheumatic diseases PMID: 24152419

Because pain is involved, I am including demonstration links only for triboluminescence.
For more information, see:

Counter irritants –

Gout –

Acupuncture –

Methyl salicylate triboluminescence –

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 -