Wednesday, May 28, 2014

Cold Receptors Come In From The Cold

Biology concepts – thermosensing, cool sensing, allergy, cross-reactivity, cold allergy, sperm maturation, acrosome reaction, opiate withdrawal

You can be allergic to things that touch your skin – like poison ivy,
things injected, like bee venom, things eaten – like foods, or things
inhaled – like perfumes. But now we need to add something else
to this list – cold? On the right you see a common way to test for
allergy. Anything that produces a wheal and flare reaction
(blanched and raised surrounded by red) is considered positive.
But what if they’re just allergic to the metal needle? 
Allergies can result when your immune system, specifically your mast cells, have an exaggerated response to something that should be innocuous. We have talked about the different kinds of immune hypersensitivity reactions before, but in general, allergy (or atopy, from Greek for out of place) occurs when your body produces a type of antibody (IgE) that recognizes foreign substances and causes your mast cells to release histamine.

Histamine release can lead to itching, watery eyes, runny nose, and even hives (urticaria, from Latin for nettle, see the post on nettle toxins). The IgE is good for helping you learn to avoid poisons and such, but what if your body makes and IgE to something that isn’t dangerous, like peanuts or latex?

Sometimes it isn’t even a case of building an antibody to something that is normally not deemed foreign. Sometimes a peanut molecule just looks enough like some other antigen that an IgE is tricked into binding to the peanut molecule or the banana molecule.

The fruit-latex syndrome is a good example of this. In many cases of people being allergic to latex (Hevea brasiliensis), they also have an allergy to avocados, kiwi fruit, bananas, or chestnuts. The IgE that recognizes the latex hevein protein cross reacts with a beta-glucanase enzyme protein from the fruits.

In the cases of cross-reacting antibodies, there are antibodies to innocuous antigens, your body reacts to them just like they were something dangerous. Histamine release results from IgEs grouping around an allergen and then attaching to a mast cell. If you have encountered this allergen before and have ramped up the number of IgEs that recognize this antigen, the mechanisms can lead to anaphylaxis. This life threatening condition is marked by inflammation that can cut off airways and a lowering of blood pressure that could kill the brain.

Spina bifida patients often develop latex and tropical fruit allergies.
Spina bifida is an incomplete closing of the spinal cord in the fetus
and can lead to severe difficulties in leg movement. It can range from
undetectable to very evident, like in the right image above. Lots of
treatment means lots of chances to develop latex hypersensitivity,
and almost 2/3 of spina bifida patients develop a latex allergy. A 2011
study says that they first develop allergy to latex, and then this cross-
reacts with the fruit. So patients without latex allergy don’t have
to avoid the fruits.
People allergic to nuts or bee stings are forced to carry around injectors of epinephrine just in case their allergies are triggered. The epinephrine constricts blood vessels, increases the heart rate and the amount of blood moved, so your blood pressure won’t drop too far if you take it soon enough. It also dilates the airways and stops inflammation so you can keep breathing. These are all good things.

Like we said, this is how allergies can and sometimes do work. But there are exceptions. Did you know that you can be allergic to cold weather? Yes, I hear you out there, chuckling that you’ve been allergic to shoveling snow for years. But what I’m talking about is a physical allergy – hives, breathing problems, itching, and cough – just because your skin and airways are exposed to cold air.

No – you can’t make an antibody to an environmental condition like cold – at least not as far as I know. But remember that TRPM8 is a cool sensor, stimulated by cold temperatures. What if your body skipped the antibody part and the cold temperature itself stimulated mast cell degranulation (release of histamine granules)? Maybe it does, but whether the cold acts via TRPM8 is another question.

Mast cells (in red) degranulate in response to allergens.
The allergen (1) is recognized and bound by the
appropriate IgE antibodies (2). The end of the antibody
opposite the allergen binding site has a receptor on the
mast cell surface (3). Crosslinking of more than one
surface recpeotr with Ab causes degranulation and
release of inflammatory mediators, like histamine (4)
from the granules usually stored in the cytoplasm (5).
There are only a couple of studies that have looked at TRPM8 and cold-induced urticaria. In 2010, a study using rat mast cells showed that they do express YRPM8 ion channels and that they do release histamine when exposed to cold or methanol (a TRPM8 agonist). The histamine release could be blocked, even at cold temperatures, by treating the cells with a TRPM8 antagonist. Pretty convincing, eh?

But the very next year, another study said it was unlikely that TRPM8 was responsible for cold-induced urticaria. This study used human mast cells and mice. Although they did find TRPM8 channels on the mouse mast cells, they didn’t release histamine in the presence of cold in their experimental model. And the researchers didn’t even find TRPM8 expressed on the human cells. This is a bit unusual, since mice are usually a great model for human physiology.

In mast cells from mice with no TRPM8 channels (TRPM8 knockout mice), the mast cell response to cold was normal, so this study concluded that TRPM8 is not involved in cold urticaria. Confusing, but a good opportunity to cheer the relentlessness of science. Study will continue until something is repeatable and can’t be proved wrong. Maybe it will be you – curing cold allergy might not make you rich, but cold-triggered asthma follows a similar stimulation – and solving that little problem will get you a Nobel Prize and a big fat check.

How about another exception? One important difference between TRPV1 warm/hot sensor and TRPM8 cool/cold sensor is that TRPV1 is often located on pain neurons, while TRPM8 is located on other types of neurons and other cell types. TRPM8 activation is not associated with pain sensation directly, since they don’t help depolarize pain neurons. But there is an exception – your teeth.

The left cartoon shows the dentinal pores and how they have
odontoblast processes in them. If the dentin is expose by
receding gums or by decay, the pores are then exposed. On
the right, different stimuli can cause the fluid in the pores to
move, which then puts strain or stretch on the processes, this
causes shifts in ions and that can cause the neurons to fire. These
neurons only carry one message – pain.
Inside the middle of each tooth is the pulp (in the pulp chamber), made up of a few layers of cells that can make more tooth material (odontoblasts), some blood vessels, and a set of nerves. Odontoblasts make a product called dentin, which is hard, but not as hard as enamel. The enamel on your teeth is not very thick, most of the structure is dentin. As you age, insults to the tooth (like decay), can stimulate the laying down of additional layers of dentin inside the pulp chamber.

The dentin has minute pores that travel out from the middle to the base of the enamel layer. If decay or some other stimulus reaches the pore, processes (like fingers) of the odontoblasts in the pores can react to the stimuli. These then signal the neurons in the pulp. However, the pulp has only pain sensing neurons. So every stimulus that reaches the pulp will be interpreted as pain.

The odontoblasts have TRPV1 channels, TRPM8 channels and TRPA1 channels (we will talk more about these next week). The hydrodynamic theory of tooth pain says that the changes in temperature that reach the odontoblast processes result in pressure changes and this puts mechanical stress (stretch or shear) on the membranes. These then trigger the channels and the signal is passed to the pain neuron.

A 2013 PLoS study says this is partially true. Their results seem to indicate that very cold and very hot stimuli do produce mechanical pressure on the membrane, so TRPV1 and TRPA1 are responsible for mechano-sensitive pain. But they suggest that in the case of TRPM8, cool/cold temperatures trigger the odontoblasts and neuron. The neuron only has one thing to say - pain – so when triggered by TRPM8 signals in the neighboring odontoblast, it responds the only way it knows how. Too bad, but it has spawned a million dollar industry in toothpastes for people with sensitive teeth.

This is a cartoon of the head of a sea urchin sperm, but many
of the concepts apply in humans as well. See all the red
arrows? Those represent the places where calcium flux is
important in maturation and function. And what do TRPV1
and TRPM8 move the best – calcium. The acrosome reaction
actually dissolved the membrane around the acrosome so that
it can more easily enter the ova. This has to be done at a proper
time; TRPM8 activation prevents it from happening too early.
Here’s another TRPM8 function that we will touch on only briefly. We talked about TRPV1 being important in sperm maturation and in entry into the egg. Well, it looks like TRPM8 is involved as well, only in the opposite direction. TRPM8 signaling, according to a 2011 study, TRPM8 activation prevents sperm maturation. This is also important, you need the capacitation and the acrosome reaction to occur at the proper point because they shorten the sperm survival time.

TRPM8 signaling prevents the acrosome reaction, but when the egg is near, a chemical called CRISP4 is released from the egg or parts near there. CRISP4 is a TRPM8 inhibitor. When TRPM8 is inhibited, now TRPV1 can be stimulated to trigger the acrosome reaction.

The interesting part here is that up to the point of CRISP4 release, something is constantly stimulating TRPM8 activity in the sperm cell. I really doubt that there's a cold stimulus way up inside the uterus, so just what is activating TRPM8? We know about lots of endogenous activators of TRPV1, but there has only been one study saying that TRPM8 might have a body-produced agonist, a type of lipid called lysophopholipids. But I think we are missing a bunch of other agonists – maybe you could look for those someday.

OK, here’s the last weird function for TRPM8 today. Would you believe it works in morphine action and withdrawal (when addicted)? Opiates like morphine are analgesic and cold antinociceptive. You take morphine and you don’t sense cold – of course, you won’t sense much of anything else either. For cold, we know how it acts. Opiates cause the internalization of TRPM8 channels on neurons. If there are no exposed channels, they can’t be triggered to allow ions into the neuron.

It goes even further; this isn’t some byproduct or side effect. Menthol is known to create analgesia (one of the reasons they use it in cigarettes). But according to a 2013 paper, if you give naloxone (an opiate blocker) at the same time as menthol – no analgesia. TRPM8 internalization is required for morphine to work.

The term, “cold turkey” is fairly old, first appearing in print
around 1910. It means “without preparation,” but just where
it came from is a matter of question. It might refer to the fact
that cold turkey after Thanksgiving doesn’t need preparation.
It might also be related to “talk turkey, which means to get
down to business. But the way that drug addicts feel cold,
sweat, are pale and have goose bumps – the visual aspect is
not wasted. By the way – who would smoke a cold turkey?
This is important when you are trying to kick a morphine habit. As you stop taking the opiates, TRPM8 quickly relocates to the membrane of the cell and is very easily activated. This causes a cold hypersensitivity and hyperalgesia. People going through withdrawal feel cold because their TRPM8 channels are firing. This is one explanation for calling it, “going cold turkey.” It is uncomfortable and painful, and is one of the main reasons that patients fail detox.

The naloxone that is used to treat morphine addiction binds to the opioid receptor, but doesn’t produce the analgesia. It also allows the TRPM8 to remain externalized, so they don’t have the rebound feeling of cold and pain. Pretty impressive – and now you know how it works.

Next week – TRPM8 is for cold, then there’s the cold that hurts. That is a different receptor, called TRPA1. It makes cold hurt, abut it also saves you from the cold.

Gibbs GM, Orta G, Reddy T, Koppers AJ, Martínez-López P, de la Vega-Beltràn JL, Lo JC, Veldhuis N, Jamsai D, McIntyre P, Darszon A, & O'Bryan MK (2011). Cysteine-rich secretory protein 4 is an inhibitor of transient receptor potential M8 with a role in establishing sperm function. Proceedings of the National Academy of Sciences of the United States of America, 108 (17), 7034-9 PMID: 21482758

Shapovalov G, Gkika D, Devilliers M, Kondratskyi A, Gordienko D, Busserolles J, Bokhobza A, Eschalier A, Skryma R, & Prevarskaya N (2013). Opiates modulate thermosensation by internalizing cold receptor TRPM8. Cell reports, 4 (3), 504-15 PMID: 23911290

Medic N, Desai A, Komarow H, Burch LH, Bandara G, Beaven MA, Metcalfe DD, & Gilfillan AM (2011). Examination of the role of TRPM8 in human mast cell activation and its relevance to the etiology of cold-induced urticaria. Cell calcium, 50 (5), 473-80 PMID: 21906810

Cho Y, Jang Y, Yang YD, Lee CH, Lee Y, & Oh U (2010). TRPM8 mediates cold and menthol allergies associated with mast cell activation. Cell calcium, 48 (4), 202-8 PMID: 20934218

For more information or classroom activities, see:

Cold allergy –

Hydrodynamic theory of tooth pain –

Sperm maturation –

Drug withdrawal –


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