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Evolved to Feel No Pain?

At-a-Glance

  • Researchers studying mole-rats have found several with insensitivity to different pain-causing substances.
  • The Highveld mole-rat is the first mammal known to have pain insensitivity to AITC, the pain-causing chemical in wasabi and other horseradish.
  • The differing pain insensitivities among the different mole-rats (and one root rat) all seem to be perfectly designed and suited to their post-fall diet and habitat.
  • Although only hinted at in the abstract of the paper, by studying what causes these mole-rats to be insensitive to pain from different substances, researchers hope to develop medicines for humans which can block or manage pain.

We’ve previously reported on the ability of naked mole-rats to survive in anoxic conditions and briefly mentioned their pain resistance, but a new study looked at other mole-rats to see if there were additional substances which they were insensitive or resistant to. It turns out that the highveld mole-rat is insensitive to allyl isothiocyanate (AITC hereafter). AITC is the “spicy” compound in horseradish and wasabi, the one which makes your nasal passages and eyes sting if too much is eaten at once. In addition, the highveld mole-rat has a significantly blunted pain response to capsaicin and also formic acid. Other mole-rats tested also yielded more pain insensitivity data.

Varying Pain Insensitivity in Mole-Rats

In the study, eight species of mole-rats (from five different genera), one species of East African root rat, and a common mouse were used as test subjects. The test subjects were injected in the paw with either a saline solution or a PBS (buffered salt) solution1 as a control. Then they were also injected with either capsaicin (what makes hot peppers spicy), dilute hydrochloric acid (HCl), allyl isothiocyanate (AITC), and lastly a few rodents were injected with formic acid (a common irritant that stinging insects use).2

The researchers estimated pain in the rodents by whether they licked their paws or “flicked” them (hopping around or shaking their paws).3 In addition to physical tests on the animals, the researchers also took three samples from each rodent species of sensory tissue—dorsal root ganglia, and spinal cord tissue.4 They then extracted RNA from these tissue samples to be compared against each other after the live animals were tested.

The researchers wanted to see if other mole-rats showed the same pain insensitivity as the naked mole-rat to the same and also to different substances. It turns out that some mole-rats and the root rat displayed a diverse array of reactions to the different irritants. As the researchers had previously shown, the naked mole-rat was insensitive to capsaicin and weak HCl.5 The new study showed that the Natal mole-rat (Cryptomys hottentotus natalensis) was insensitive to capsaicin, the Cape mole-rat (Georychus capensis) and East African root rat (Tachyoryctes splendens) were insensitive to weak HCl acid, and the highveld mole-rat (Cryptomys hottentotus pretoriae) was insensitive to AITC. Also, they discovered that three mole-rats displayed no pain-insensitivity (Damaraland, Mahali, and Common mole-rats).6

It turns out that some mole-rats and the root rat displayed a diverse array of reactions to the different irritants.

Highveld Mole-Rats Designed to Do What They Do (and Where They Do It)

The highveld mole-rat is a furry cousin to the more famous naked mole-rat and is now the only known animal to be pain insensitive to AITC. In addition, it also showed more pain resistance to capsaicin, although it showed the same pain response to weak HCl as all other rodents not pain insensitive to that substance. But another surprising result was that the highveld mole-rat was also insensitive to formic acid, and it showed pain insensitivity initially to a formalin injection. Formalin is a liquid mixture of formaldehyde, water, and about 10–15% methyl alcohol. Formalin elicits a two-phase pain response—an acute stage for 0–15 minutes and then followed by a prolonged, but less severe second phase (15 to 90 min). The highveld mole-rat showed no pain response to the first 15-minute acute phase but did have a normal pain response to the second phase.

The researchers had theorized that because the highveld mole-rat often shared its burrows with Natal droptail ants, which bite and inject formic acid into the wound, that highveld mole-rats would show some type of resistance to formic acid (and they turned out to be right). In another step, they crushed up the abdomens of the droptail ants, put them into a liquid and injected them into several of the mole-rats and the mouse, and only the highveld was insensitive to that concoction.7

AITC is known to cause pain by activating the sensory transient receptor potential channel (TRPA1 hereafter). In fact, sensitivity to it is known to exist in all mammals (except now, the highveld mole-rat). So, the researchers decided to see how the highveld mole-rat acquired this pain insensitivity. When they looked at the molecular markers of neuropeptidergic neurons8 that encode the AITC-gated TRPA1 ion channel, they found it was expressed at comparable levels in all species, including the highveld mole-rat.9 That allowed them to rule out a mere absence of transcripts as the cause of the pain insensitivity. After comparing the dorsal root ganglia tissue of the highveld with the Natal mole-rat’s sensory tissues, they found that in the Nalcn gene, mRNA levels were substantially higher in highveld mole-rat tissue than in Natal mole-rat tissue. The researchers then hypothesized that the overexpression of the sodium leak channel, NALCN, in sensory neurons may be the main contributor to AITC-insensitivity. In cultured cells, the overexpressed highveld sodium leak channels acted as an electro-chemical mechanism for dampening the activation of TRPA1 (which then promotes pain insensitivity to AITC).

To test this hypothesis, they blocked the NALCN channel by administering verapamil and when repeating AITC pain tests discovered that the highveld mole-rat suddenly became sensitive to AITC. But they also ran subsequent tests and found that the pain response only lasted 24 hours, after which time highveld mole-rats regained their pain insensitivity. They also injected verapamil into the highvelds before testing them against the ant concoction, formic acid, and formalin, and the highveld mole-rats all elicited a pain response, but in these cases it only took an hour to regain pain insensitivity.

So, what would be the evolutionary explanation for the several different pain insensitivities in several genera and species of mole-rats (and one root rat)?

So, what would be the evolutionary explanation for the several different pain insensitivities in several genera and species of mole-rats (and one root rat)? In the discussion section at the end of the paper, the authors lay this out.

“In contrast to birds, which have a capsaicin-insensitive TRPV1 (42, 43), both the naked mole-rat and Natal mole-rat are insensitive to capsaicin but likely possess capsaicin-sensitive nociceptors. Acid insensitivity was observed in three species that are separated by more than 40 million years of evolutionary history but has resulted partly from changes in the expression of many genes, several of which, like the downregulation of TWIK1 and ASIC3 would clearly blunt acid excitation of nociceptors [a sensory receptor for painful stimuli].10

“In the case of the highveld mole-rat, we have provided evidence for stepwise molecular changes that combine selection of TRPA1 channels with poor AITC sensitivity with a major change in the expression of a second channel protein NALCN to effectively silence chemical nociception [the nervous system’s response to painful stimuli]. The coordinated molecular changes leading to pain insensitivity in the highveld mole-rat likely occurred over a period of less than 7 million years and were likely driven by a combination of environmental factors, including pungent food sources and coexistence with aggressive stinging ants.”11

The Evolutionary Problem of Explaining Pain Insensitivity in Mole-Rats

In an evolutionary worldview it certainly seems curious that several genera of mole-rats and a root rat would develop pain insensitivity to (in some cases) the same pain-causing agent (algogen), and in other cases different algogens. Additionally, some species had no pain insensitivity to any of the algogens. Furthermore, the mechanism by which they gained this pain insensitivity seems to be different in several species. Sometimes it is a gene being switched off, other times it is suppressing a expression of a gene, and finally in the highveld mole-rats it is a channel protein being silenced.

Furthermore, their supposed evolutionary age of the mole-rats and root rat show no correlation with pain insensitivity. The “oldest” rodent, the control mouse has no pain insensitivity, while the “oldest” mole-rats and root rat do show pain insensitivity. The mole-rats in the middle of the evolutionary age spectrum all show no pain insensitivity, while the “youngest” mole-rats, the natal and highveld also have pain insensitivities. See the following table for a comparison of the alleged evolutionary ages and the varying pain insensitivities of the rodents.

Insensitive to compounds below Naked mole-rat Highveld mole-rat Cape mole-rat Natal mole-rat Root rat Other mole rats Mouse
Capsaicin X     X      
AITC   X          
HCl X   X   X    
Formalin   X (for first 15 minutes)          
Formic acid/ant slurry   X          
Environment, e.g. coexistence with ants   X          
Supposed evolutionary factors, e.g. ancestry/age 3 7 4 6 2 5 1
(Numbers indicate alleged evolutionary order)              

Created to Thrive

In a creation worldview, this is merely speciation from at most two created mole-rat kinds (Spalacidae and Bathyergidae), and then adaptation in a post-fall and post-flood world. Mole-rats would have been created with a very diverse genome and the original created kind(s) might have had pain insensitivity to several environmental factors built in. The other possibility would be that they were able to rapidly adapt to post-fall conditions as a result of their originally created diverse genome. Since God cursed the ground and mentioned the thorns and thistles which would now be prevalent (Genesis 3:17–18), it is quite possible that many “plant defenses,” including chemical ones, came into being at this time (immediately after the fall). For a fossorial (burrowing) animal which subsists on plants (and in a post-fall world, also insects), it would be advantageous for these animals to have some sort of pain resistance or pain insensitivity in order to thrive. And by studying these creatures’ pain insensitivity, researchers may be able to develop medicines or treatments to block or treat pain in humans. Most likely, the extant mole-rats have lost pain insensitivity through speciation and only retained the ones they need in order to survive based on diet, location, and animals they frequently encounter. But whether through originally created heterozygosity winnowed through speciation or post-flood adaptation, these are not molecules-to-man evolutionary changes. Mole-rats remain mole-rats, albeit with different abilities to withstand pain.

Mole-rats remain mole-rats, albeit with different abilities to withstand pain.

The latter half of Psalm 104 describes how God provides for animals in a post-fall world. Knowing their dietary and lifestyle needs, God provides for their sustenance. Even in a world of poisonous plants, biting ants, and stinging nettles, God makes sure that every animal is provided for, and can turn these barriers into “good things.”

The young lions roar for their prey, seeking their food from God. When the sun rises, they steal away and lie down in their dens. Man goes out to his work and to his labor until the evening. O LORD, how manifold are your works! In wisdom have you made them all; the earth is full of your creatures (Psalm 104:21–24).

These all look to you, to give them their food in due season. When you give it to them, they gather it up; when you open your hand, they are filled with good things (Psalm 104:27–28).

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