Some years ago, after putting out the recycling, I had the unpleasant discovery that my dog had got into my bag of jalapeño potato chips and thrown up all over the floor. They obviously hadn't sat well with him. As I cleaned up the mess, I pondered why my dog was so quick to expel the snacks, whereas I could happily eat a whole bag in a single sitting. Evidently, the same question occurred to Ole Eigenbrod of the Max Delbrück Center, Germany, who teamed up with a group of international collaborators to explain why some animals tolerate certain substances, whereas others do not.
The nervous system perceives pain via specialized neurons (nociceptors) that respond to substances ranging from lethal venom to benign pepper. However, even closely related species do not respond with equal intensity to the same compounds, thanks to their different evolutionary trajectories. For this reason, Eigenbrod and colleagues studied pain insensitivity in nine species of related African burrowing rodents, which are separated by 7–55 million years of evolutionary history, by evaluating their reactions to three noxious molecules: capsaicin (which makes jalapeños spicy), hydrochloric acid (found in acidic fruits) and AITC (a pungent molecule in many root vegetables). After dabbing a stinging molecule onto each animal's footpad, the authors assessed how much pain they experienced by measuring the time each rodent spent licking its paw. They also investigated the molecular components of the rodent's pain neurons, to identify the specific differences that underlie pain insensitivity.
The researchers initially found that the pain neurons of all nine rodent species possess the receptor molecules that should allow them to detect the three noxious molecules. However, some of the species did not exhibit pain in response to these compounds. For instance, highveld mole-rats did not feel AITC dabbed onto their paws, even though there are neuron receptors that should bind the noxious chemical and potentially trigger pain. The team attributes this insensitivity to the overexpression of a gene for a sodium leak ion channel that short circuits the pain neurons and prevents them from transmitting signals. The team suspects that AITC resistance stems from the highveld mole-rats sharing their burrows with aggressive Natal droptail ants, whose excruciatingly painful stings activate the AITC receptor. Clearly, it was advantageous for the rodents to evolve immunity to the stings.
The team also observed that East African root-rats, Cape mole-rats and naked mole-rats were completely oblivious to the hydrochloric acid dabbed onto their paws. The authors found that the pain neurons of these three species possess a sodium ion channel with the same two amino acid alterations. These changes prevent hydrochloric acid from activating the ion channel, rendering the neurons insensitive to the acid and unable to trigger pain. Considering that the three species are separated by 40 million years of evolutionary history, these modifications are a classic case of convergent evolution, allowing all three species to tolerate hydrochloric acid.
Finally, the researchers noted that Natal and naked mole-rats are impervious to the spicy jalapeño capsaicin and believe the rodents’ evolved insensitivity is due to them inhabiting deep, oxygen-poor burrows, where CO2 levels can reach very high levels. Given that inhaling large amounts of CO2 can cause a great deal of pain, it is likely that the mole-rats adapted to their underground lifestyle by blunting most of their pain responses.
Although the nine rodent species are closely related, they each live in very different geographical environments and have faced different selection pressures that have led to their varying degrees of pain sensitivity. It appears that evolution has several lessons to teach us about the various molecular mechanisms that can mediate pain.
