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.
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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.
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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.
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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.
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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?
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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?
Next week, more functions of TRPV1 – it can make pain worse and stop pain. How can that be?
For
more information or classroom activities, see:
Agonist/antagonist
–
Eugenol
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Gingerol
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camphor
-
tonicity
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