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The Proteins of Pain: Part 2, Threatening Spice (Member Post)

 •  • by Paul Ingraham
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Weekly nuggets of pain science news and insight, usually 100-300 words, with the occasional longer post. The blog is the “director’s commentary” on the core content of a library of major articles and books about common painful problems and popular treatments. See the blog archives or updates for the whole site.

Recently I bought this capsaicin product for the first time:

I was oblivious to the long history of this brand’s cultural appropriation, going back to the mid-2000s. But I wanted to test capsaicin on my Achilles tendinitis — another problem with a history going back to the mid-2000s. But this was the only product on the shelf that actually had capsaicin (the Tiger Balm and A535 did not).

Why was I keen to test capsaicin? Because of the Nobel-prize winning discovery of the receptor that detects the stuff! In mid-October I wrote about “the proteins that help us feel the world,” the molecular machines that create sensations from heat and pressure — plus plenty of “other,” including spice.

This is part two. What do these receptors have to do with pain? Quite a lot! Honestly, two parts is not enough. There’s going to be a third.

Last month on The Proteins That Help Us Feel the World

  • “Transduction” is the conversion of physical forces into nerve impulses.
  • Proteins are the main transducers. Embedded in nerve cell membranes like pores, they open in response to stimuli like heat; that lets ions flood into the neuron, triggering a nerve impulse.
  • The TRPV1 channel opens for scalding heat, spice (capsaicin), acidic conditions, inflammatory molecules, and more.
  • The Piezo1 and Piezo2 proteins react to physical deformation of cell membranes: pressure and stretch.
  • And all of this is about pain, too… because extremes of temperature and force are dangerous, and pain is fundamentally an alarm system.
  • The transduction of potentially noxious stimuli is “nociception,” another highly relevant topic I wrote about recently.

My outrageously oversimplifying title: of all the nerve!

I have expert readers who will scowl disapprovingly at my title. Well, turn that frown upside down, experts! We’re going to use the simplicity to teach the complexity. The title is a deliberate, whimsical, snappy summary of the much more complex truth it hangs over, like a neon sign that tempts but leaves much to the imagination. Inquire within.

They are not “pain” proteins, of course, but “data” proteins — they transduce information about the state of tissues that could be interpreted as pain, later, after submitting an application in triplicate to the rest of the nervous system. But many kinds of painful experiences would never happen without these proteins: they are linked by a clear chain of causality. Viewed from a high altitude, the details blurred, they are “pain proteins.”

The more accurate title: “The Proteins That Transduce Several Potentially Noxious Stimuli Which May or May Not Be Eventually Produce the Neural Output Pattern Known as Pain.”

It’s a bit wordy, though, and notably still leaves out a lot of important detail.

Slow-motion capsaicin craziness

The first time I used actual capsaicin on my poor tendons, nothing at happened at all for a whole afternoon — no sensation. I may as well have applied moisturizer. A second modest dose produced only a slight tingling that evening. I went to bed with mildly toasty heels… and then woke up with over-toasted heels.

They felt like they had actually been burned. It was awful. I did not sleep well that night. “Therapy.”


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The strange delay was not a fluke. When I dared to try again a week later, it all happened again. A single small dose midafternoon was undetectable for the rest of the day, but then I was awoken by pain at 2AM that blasted a three-hour hole in my night. Oops. Not worth it!

So what the heck is up with these capsaicin receptors, and what was I hoping to achieve? I will circle back to this. But this experience “inspired” me to dive into this topic again. It synchronized perfectly with the protein science.

Brief housekeeping note for premium subscribers

One of my original ideas for premium posts is that some would be longer — just me setting my intellectual enthusiasm loose on a topic, diving as deep as I want to dive, and bringing you along for the ride. This post is a perfect example. It’s been slow getting it out the door, because it’s so big (and there’s still a part 3).

But I have also been preoccupied with a big project: giving you extra benefits, not just a newsletter, making you all into “members” rather than just “subscribers.” The big thing is to give you access to a bunch of members-only content around PainSci. It’s basically done — the guts are there, and they mostly work. I have some bugs to squash and some polishing to do.

The official announcement coming soon in another post, plus more about three other ideas I’m considering:

  1. Separate newsletters and pricing for patients and pros.
  2. Ask-me-anything video meetings for members only.
  3. A slower publication pace. Quality and speed do not play well together, and we all have too much to read anyway, amiright?

If you have feedback on any of those ideas, let me know!

The proteins of danger!

Being an organism is perilous. Every living thing needs to know when it’s being poked, specifically and especially whether or not it is being done too hard. We also have to know when it’s too hot or too cold. Pressure and temperature detection are about as elementary as sensation gets. Many simple organisms can do as much, even the ones that have only a single cell.

Extremes of pressure and temperature are usually experienced as an alarm — as pain — ideally before any damage is done.

Of course we also need to know when it’s too late and we’ve actually been damaged — nothing is more dangerous than already being hurt (because it involves serious vulnerability to getting hurt even more). And these receptors are partially involved in that too. For instance, TRPV1 also reacts to inflammation.

Almost everything biology has eighteen jobs.

TRPV1 also detects … spice. Which is not threatening, but absolutely can feel like it. But spiciness is not for the birds… which is why the plants use it! An explanation of that weird sentence below.

Also: How hot can you take your bath? How can the same pressure be bliss for one person and torture for another? Finally I will track the biological oddity of spicy heat to a cool clinical question: can we exploit the nature of TRPV1 receptors to treat pain?

Threatening heat

What is “scalding” heat? 40˚ Celcius is the low end. That’s the temperature, roughly, that opens TRPV1 ion channels — a temperature right on the edge of what’s tolerable.

How do hot do you like your hot tub? 40˚ is about as high as most people want to go, and some don’t even want that (my wife again). I am fine at 40˚, wincing at 41˚ but still loving it, and I start to struggle at 42˚. In the space of 3 degrees, my reaction goes from “meh” to “ack!” All thanks to more and more TRPV1 receptors getting triggered.

Note that 40˚ is also the temperature a high fever. Curious that we have a protein dedicated to detecting our maximum tolerable temperature — inside or out. Curious & a bit profound.

Hot tap water ranges from 38–45. My home’s tap water is at the high end, and I can barely wash my hands in it — I can only do it fast, saying “Ooh ooh ooh!” My wife won’t touch it.

But “some like it hot”

Whether there’s enough heat to feel painful is partially just a matter of literal degrees. More degrees means more TRPV1 reacting. On a cold day, your TRPV1 proteins are mostly still and quiet. In a scalding hot shower, billions of them are getting busy. If you are actually scalded and burned… trillions.

But it’s not just quantity, it’s also context. If someone aggressively rushed up to you on the street and threw a bucket of 41˚ water on you, you’d scream like you were being burned alive — even though that cannot actually damage you. On the other hand, you can slip into a 46˚ steam room and think it’s bliss, at least at first… but that actually can burn you.

That’s the brain getting involved in interpreting the potential meaning of all that TRPV1 signalling, and modulating our perception accordingly. And aside from the temperature itself, the most important contextual clues are the area of skin exposed to scalding heat and how quickly that exposure happens.

Rapid full-body immersion in 42˚water is brutal — most people just can’t do it. But slowly inserting just your hands into a sink at 44˚ is no problem at all for most people. The rate and extent of the activation of TRPV1 receptors are valuable clues about potential threats that the brain takes super seriously.

It’s a trap!

Threatening pressure and stepping on Lego

Stepping on a piece of Lego is notoriously painful, and there’s a whole class of painful experiences like this: insults that seem to hurt out of proportion to how dangerous they are. Sharp and sudden pressure seems to lead the pack.

Piezo1 and Piezo2 are the proteins that detect that pressure.

Sudden, focal pressure is the stimulus that always precedes one of the most basic threats to any living thing: puncture! A “hull breach.” Gouged or stabbed. A hole in the integument. The most basic type of injury shared by all living things. Even single celled organisms can be ruptured — and so they retreat from anything that pushes too hard and unexpectedly on their membranes.

Lego hurts because your brain thinks:

“What if it’s a sharp stick? What if there’s more? We need to take this seriously! Pay attention! Stop walking, stop stop stop!”

We have a finely tuned alarm system for potentially dangerous stuff underfoot. As with temperature, the threat is mostly proportionate to how strongly receptors are activated, but also very sensitive to area and rate. Only in the case of pressure, it’s smaller areas of higher pressure that, contextually, are of greater concern to the brain — because of the puncture peril.

Unless it’s a friendly thumb…

Putting pressure in context

🎶 Mmm num ba de
Dum bum ba be
Doo buh dum ba beh beh
Pressure pushing down on me
Pressing down on you, no man ask for
Under pressure that burns a building down
Splits a family in two
Puts people on streets

“Under Pressure” (Queen, David Bowie)

One of the most curious things I noticed early in my career as a massage therapist was the startling diversity of pressure tolerance. This may be accounted for by genetic and pathological variations in the sensitivity of the pressure receptors, Piezo1 and Piezo2. Their sensitivity varies widely with many variables. I was unable to confirm that there is a genetic variation that makes them more sensitive (without ruining us in some other way), but it would be surprising if there were not global average differences in how easily triggered these receptors are.

Just as some people are “super tasters,” it’s a near certainty that some people are “super pressure feelers.” This is a good thing for massage therapists to bear in mind.

But the context of pressure is also vital, and massage is one of the most obvious examples. Intense pressures can be highly pleasurable… even when it is actually doing harm (contusions, sometimes probably severe enough to cause rhabdomyolysis, poisoning by the release of muscle proteins into the blood). This is a fascinating and quite a rare example of context completely over-riding a legitimate safety alarm!

Sometimes the brain gets it wrong.

Where are all these receptors anyway?

These receptor proteins are sprinkled everywhere in human physiology, but they are clustered the most thickly on nociceptors — the nerves most specialized for detecting potentially dangerous stimuli. And they are the thickest of all where they are most likely to encounter the stimuli they exist to detect — so there’s a lot of them in the skin.

Piezo1 and Piezo2 are also dense in the walls of hollow organs. To detect stretch. How else will you know when it’s time to pee?

Abused term #1: “pain receptors”

Some people will call these proteins and their host nerves “pain receptors,” but that’s definitely oversimplifying things dramatically, to the point of error (even more so than my “proteins of pain” title).

Pain is not a thing in the world to be detected. Even the output of nociceptors is not yet pain, let alone the input.

Proteins transduce the stimuli, they don’t interpret it. The nerve cells pass the message along, but they don’t editorialize.

Abused term #2: “noxious stimuli”

The term “noxious stimuli” is similarly abused, as if it was the same thing as pain. But these stimuli are not inherently noxious — they are only threatening in excess or depending on what caused them. Both heat and pressure can easily be excessive and dangerous, but usually these stimuli are minimal and completely safe… and yet still extremely useful.

For instance, squirming is inspired by the information we get from pressure receptors. We are bombarded by constant low-priority data about the need to shift position because there’s been some pressure on this or that spot for too long. It’s nowhere close to “dangerous” yet — but if we didn’t move, those spots would become pressure sores.

What is up with the bizarre delay in capsaicin burning that I experienced?

I have no idea. I am open to yours!

Zero sensory effect for up to 12 hours, followed by savage burning. From a modest dose. I am genuinely baffled.

I have experienced no relief from my Achilles tendinitis pain. I didn't really expect to after just a few applications, but for the record. There will be plenty more to say about how capsaicin might be therapeutic in part three.

But first, to wrap up part two, some genuinely fascinating spice science.

Threatening spice: TRPV1’s spicy side effect

TRPV1 is also a capsaicin detector… by accident. It responds to capsaicin, the active ingredient in all kinds of chili peppers. The response is proportionate to the dose, and it can be potent indeed, but we can detect even teensy traces of capsaicin in places that have many TRPV1 receptors, like tongues. And eyeballs.

My father, a Vietnam veteran, has a great story about a wild pepper he encountered in the jungle. He used it to liven up his C-ration, which it sure did. But after chopping the mystery chili, he rubbed an eye … and was effectively blind in that eye for about a day.

Good as we are at detecting capsaicin, it's mostly harmless. It feels much more toxic than it is. Even large doses of capsaicin are surprisingly harmless — even people who get pepper sprayed right in the eyes can fully recover.

So what’s going on? Why the sensitivity to something that isn’t actually much of a threat?

It’s probably a bug, not a feature — our branch of the tree of life is just good at detecting this stuff by accident, a side effect of how our heat transduction works. But nature has made good use of it anyway, as explained by Nature in 2001. Plants probably produce capsaicin because it “selectively discourages vertebrate predators” — they mean us, because we happen to be sensitive to the stuff — but “without deterring more effective seed dispersers,” like birds, who happen not to be sensitive to capsaicin.

You cannot irritate a bird with spice. They just do not care.

So here’s a thing that can cause pain — not because it’s a threat, but because it sets off the same receptor that does detect dangerous heat. That makes it really interesting. It means that it feels a lot more harmful than it is, and therefore that context is a major factor in how we experience it.

With spice, context is the whole enchilada

Your brain is aware that the “scalding” heat on your arm is actually just Tiger Balm, and not a burning hot ember from a campfire. It doesn’t need to warn you about Tiger Balm nearly as urgently. And so literally the same signal, starting with TRPV1, causing nerve impulses in nociceptors, may or may not be painful depending on… the situation.

But if you pop a whole Carolina Reaper chili into your mouth — 200 times hotter than a jalapeno — and the absurd amount of capsaicin will jam open every TRPV1 ion channel you have, generating more impulses from those nerves than your brain has ever seen… and you’re going to freak out.

I mean really freak out. The effect is harsh.

A large overdose of capsaicin is effectively indistinguishable from a serious burn, as far as the brain is concerned. While no direct harm will come of it — capsaicin is quite safe — people will suffer extreme pain, reacting as if they had actually swallowed boiling water: tremors, nausea, vomitting… for days. The pain is so intense that it probably causes panic attacks in many people (and panic attacks can often make people think they are dying).

And yet people still flirt with this experience! Because context is that powerful, and pain can literally be fun when you know it’s safe.

There’s an entire fascinating book about that: Hurts So Good. I look forward to reading and reviewing that one.

Yeah, but what can we do with all this beautiful knowledge?

There’s some lovely science here, but is it useful? Can we apply it?

Maybe. There is still plenty to say about capsaicin and TRPV1 and pain. Spiciness might actually have some therapeutic effects. Probably nothing profound — the biology is too complex and messy for a clean and easy win — but there are effects. Capsaicin does do things to us. It’s intriguing.

But that’s for part three! We’re at about 3000 words here, rarified territory for this blog… and I still have things to learn and citations to wrangle before I can continue the tour. But here are some teasers:

  • There are bizarre links between spice, marijuana, and barfing. I am not kidding.
  • There is (old) evidence that capsaicin is actually a 🤬 neurotoxin!
  • Based on the neurotoxin thing… there is an absolutely bonkers pain treatment using high-concentration capsaicin, which is insanely painful. This is not a joke. “Would you like what feels like 3rd degree burns with your insanely painful shingles?” An evil that is not clearly “lesser” than anything — even shingles!

That and more will actually be coming soon (not another month). I know this because much of it is already written. I originally thought it would be right here, right now — but it was just too much.