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Fast Pain Relief – In Only Seven Million Years

Here’s a chemical descriptor that I didn’t know: algogen, meaning a molecule that causes pain. I would have classified the natural product I did my PhD work on as one, since it caused me substantial pain at the time, but this term refers more properly to physical nociceptive types of pain, rather than the intellectual and psychological kinds. So this means things like capsaicin (from hot peppers), allyl isothiocyanate (from mustard and horseradish), concentrated acids, and so on. Nociception (pain sensation) is a mediated by a set of ancient neurological pathways whose survival benefit would seem to be obvious – you’d want to know about it when you encountered dangerous levels of heat or some noxious plant compound, and both of those lead to sharp burning sensations.

So it’s worth noticing when you discover creatures that don’t seem to care about some of these things, and the naked mole rat is one. They’re rather odd creatures in general (being a eusocial mammal is just the beginning), but the fact that they’re apparently completely insensitive to having hydrochloric acid or straight capsaicin solution dripped onto them goes pretty high up the list of oddities. Most other rodents will notice those pretty quickly and reliably, as indeed would you or I. This new paper (from a joint effort out of Germany, South Africa, Tanzania, and the US) is a followup to that work, investigated several related species of African underground rodents. (Here’s a press release from the Berlin arm of the effort).

It turns out that both the naked mole rat and the Natal mole rat are impervious to capsaicin, but the latter has no problem recognizing HCl as unpleasant. At least three other species besides the naked mole rate, though, ignore it. Meanwhile, the highveldt mole rat is even less susceptible to allyl isothiocyanate than the naked mole rat (the previous record holders; who still react a bit although far less than the rest of the burrowing rodents). That makes them the only mammal yet found that doesn’t react to AITC, a sensitivity that otherwise extends from humans through birds, reptiles, fish, flies, and all the way to planarians. So although most animals agree with us about the  desirability (extremely minimal) of being rubbed down with hot pepper extract or AITC, there are specific exceptions that can be tracked all the way down to molecular level.

Sequencing of these creatures showed some interesting changes. All of the animals seemed broadly to have the usual complement of sensory neurons (as measured by a suite of markers), and interestingly, they all had the capsaicin-sensitive Trpv1 and AITC-sensitive Trpa1 ion channels as well. (Birds are well known not to care about capsaicin, but they have Trpv1 channels that are flat-out insensitive to it). So it’s not that these things are completely missing. Instead, there are other proteins that show an association with the specific pain insensitivities: the two species that don’t mind capsaicin were both low in BMPER (bone morphogenetic protein-binding endothelial regulator), for example, and a set of 41 gene transcripts were all skewed in the same direction in the three acid-insensitive species, including a number of ion-channel-related proteins that had already been correlated with acid sensing. And the mighty highveldt mole rat, the only species indifferent to allyl isothiocyanate, showed a significant expression difference only for the sodium leak channel NALCN.

Going further down into the sequences, it turns out that the the channels like Trpa1 and NaV 1.7, while present, have specific mutations in them at the same points in their extracellular domains for the acid- and capsaicin-insensitive species. Meanwhile, the highveldt mole rat has a different set of mutations in its Trpa1, making it at least ten times less sensitive to AITC in in vitro assays. That and the upregulated NALCN (which provides an ion shunt that makes activation of the receptor far less effective) seem to account for the animal’s singular ability to ignore horseradish concentrations that send all other animals in the opposite direction. Verapamil is known as an NALCN antagonist (along with calcium channels), and the team found that verapamil-treated highveldt mole rats suddenly became just as sensitive to AITC as any other rodent (probably to their great surprise!)

Now you have to ask, “Why?” There must be some real advantage to losing what should otherwise be a useful warning system. The paper hypothesizes that some of this is driven by the burrowing rodents feeding on roots that are otherwise too pungent to eat, but the highveldt mole rat’s unusual profile appears to be driven by the constant presence of what they refer to as “particularly aggressive Natal droptail ants (Myrmicaria natalensis)”. These creatures have a notably painful bite, and crushed extract from them elicits pain responses in all the rodent species tested, except the highveldts, who don’t care. Unless they’re injected with verapamil beforehand – then they care very much.

Looking at the mutations phylogenetically, the highveldts seem to have evolved this stepwise over the last seven million years or so, which makes you think that they’ve been living down there with the stinging ants over the whole stretch, gradually becoming more and more impervious to them. So an otherwise universal mechanism gets thrown overboard by evolution in the presence of millions of years of ant bites, and we now get some new insights into pain sensing that we otherwise might never have had!

15 comments on “Fast Pain Relief – In Only Seven Million Years”

  1. NJBiologist says:

    The sodium channel finding is interesting, as it’s one of the known genetic associations for congenital insensitivity to pain. It will be interesting to read the article and see if they saw/looked for changes in TrkA, as that’s an even more prevalent cause of congenital insensitivity….

    1. Lisa says:

      They sequenced the genomes of all these critters, so one assume they looked in the obvious places.

  2. Emjeff says:

    The highveldt example with the ants is interesting. That interaction could be considered chronic pain, and it is well-known that chronic pain serves no useful purpose. So, it would stand to reason that this pain sensitivity would be selected out. Quite interesting.

  3. Nick K says:

    I found the use of verapamil to restore sensitivity of the rats to ant venom particularly elegant and convincing evidence for the proposed mechanism.

    1. Oldandstupid says:

      Oh, I remember when I was young and stupid, I once cleared an entire garden of those, disregarding the comments of my friends, because I had never heard of sunlight potentiation before. I did manage to avoid most of the sap, but I got a pretty nasty burn on my leg, about a cm wide by 10-15 cm long.

  4. sTab says:

    Naked mole rats live in large underground colonies in which high concentrations of CO2 can be generated. which can cause tissue acidification and acid-induced pain. However, naked mole rats have adapted to their habitat in a peculiar way: they possess a tripeptide sequence in the S5−S6 linker of DIV in their Nav1.7 α subunit. This enhances protoninduced blockade of these channels, thereby preventing action potential firing in the rat’s nociceptors and consequently reduced acid nociception.
    Science 2011, 334 (6062), 1557−1560.

  5. Wavefunction says:

    “There must be some real advantage to losing what should otherwise be a useful warning system.”

    Perhaps, or perhaps the loss of this system is an example of Stephen Jay Gould’s spandrels, a phenotype that’s not adaptive in itself but piggybacks on another that is.

    1. Emjeff says:

      That’s just it, though. In their world, being in constant pain from ubiquitous stinging ants that don’t permanently harm the rat is not useful at all.

      1. pv=nrt says:

        Jeff, no, you can’t conclude that it was the ants that drove the spread of this adaptation based on present data. Because of the way that physiology is constrainted by development, and how traits are inherited together, it could easily have been some other trait that was the main driver. This is a subtle point that you don’t learn until Jr year of your biology degree.

  6. MrXYZ says:

    This is really a fascinating paper. But can we translate any of these findings into new effective treatments for pain? As always, the big question is whether targets that are modulating nociceptive (protective) pain are the same targets that are modulating pathogenic pain. Or to put it another way, reducing the pain response to noxious insect bites is very different than treating the pain of a noxious insect bite once bitten.

  7. Barry says:

    Horseradish certainly is an easy plant for the gardener, but it’s not immune to deer. Dunno if they’re immune to allyl isothiocyanate. And there is the Horseradish flea beetle Phyllotreta armoraciae

  8. JG4 says:

    Speaking of evolved to tolerate stinging arthropods, there are some brilliant videos of a desert mouse being repeatedly stung in the face by a scorpion. A problem faced by desert mice in search of tasty meat for a long time. Hurts just watching.

    1. MrXYZ says:

      Here is a link to the paper where the pain resistance of the scorpion-eating grasshopper mouse is described ( It’s a fascinating study implicating mutations in another sodium channel (Nav1.8). I am fascinated by the videos as well. Hard to tell, but it looks like the sting hurts like hell at first and then quickly dissipates (which is kind of implied by the mechanism described in the paper).

  9. Bill Mc'Daniels says:

    Centrexion is working on something like this I believe. Using CAP to numb the nerv receptors.

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