Recipe for pain
Whether you are a cobra or a cocker spaniel, a raccoon or a raconteur, lots of natural, reactive chemicals will cause pain and possibly damage your cells. Even fruitflies quickly learn to shy away from sugar water that contains caffeine or chemicals found in cinnamon, cigarette smoke, onion and horseradish.
These chemicals trigger activity at receptors on cell surfaces which eventually results in an “ouch” signal being sent brain-ward.
In a study published in Nature this week, a group lead by Paul Garrity, an associate professor of biology at Brandeis University, showed that a major class of pain receptors have ancient roots. We are talking older than yesterday: the report shows that TRPA1 (transient receptor potential A1) receptor was found in the critter that spawned both vertebrates (green tree snakes, bullfrogs, dinosaurs and talk-show guests) and invertebrates (horse flies, crabs, quahog clams and talk-show hosts) at least 500 million years ago.
The investigation, spearheaded by Kyeongjin Kang in Garrity’s lab, showed that the TRPA1 receptor is so similar across the entire vert-invert realm that it must have evolved once, and then descended through countless generations without significant changes. “The fly and human proteins in this receptor appear, to a very, very high degree of significance, to be from a common ancestor,” Garrity told us.
The pain in Spain
Unlike TRPA1, many other chemical receptors, like those involved in most smell and taste, vary greatly between animals, Garrity added. “There are big families of these receptors that look quite different in different species, so there is a lot of flexibility and change, but this TRPA1 is pretty much fixed.”
When structures have remained constant over long periods, scientists conclude that the evolutionary pressures that favored them were also static. Fish retain fins because they still live in water. We retain eyes because seeing is so handy.
And the stasis of the TRPA1 receptor “suggests there has been some sort of strong evolutionary pressure in these toxic chemicals that was maintained since the receptor was invented,” says Garrity. The chemicals in question are made by plants or other organisms as self-protection, and they can damage or destroy proteins and nucleic acids, at least in high doses, and therefore are to be avoided.
Fans of horseradish and wasabi know that a nibble can be tasty but a gobble can cause an eruption of coughing.
Work by study co-author Doug Theobold, also at Brandeis, suggested the original TRPA1 receptor arose after the jellyfish branched away from our lineage about 700 million years ago. The first TRPA1 receptor was apparently present in the last common ancestor of vertebrates and invertebrates, which lived between 500 million and 550 million years ago.
And that means we may have the same tastes in food as fruitflies, but not jellyfish. “It’s bad enough to think about shooing the flies away from the sushi bar, but jellyfish, well, they may be on the menu, but I don’t want to see one on the stool,” growls the resident Why Files cynic.
How they did it
To explore the responses to these reactive chemicals, Garrity and his colleagues offered sugar water to fruit flies. Some of the water was tainted with pungent chemicals derived from cinnamon or wasabi. Some of the fruit flies had genetic mutations affecting the TRPA1 receptor. In some trials, the flies touched the toxic chemical with their legs; in others, they drank it.
Flies extend their proboscis (snout) toward something they want to eat, and the scientists measured this behavior as they offered a droplet of food five times. All flies extended the proboscis at the first offering.
After that, the rate of extension:
Plunged when any of three reactive chemicals were in the water, but only in flies with intact TRPA1 genes. Mutants with flawed TRPA1 receptors continued to reach for the water even if it contained chemicals
Curiously, when the fruitflies drank sweetened caffeine-bearing water, they turned jittery and stayed up all night, devouring junk food and cramming for a biochemistry exam. Just java jiving…
Finding such a long-term similarity in a major class of pain receptors could have broad implications, Garrity says. TRPA1 receptors exist on the aphids that spread disease to many crops and the mosquitoes that carry malaria. If compounds that trigger these receptors while sparing those of benign species can be found, they could be developed into pesticides that inflict pain and cause the nasty bugs to stay away from where they are not wanted.
A second application, which may be closer to fruition, depends on the similarity of receptors between fruit flies and mammals, Garrity says.
Compounds derived from capsaicin, the active agent in hot peppers, are already used to treat pain. Although TRPA1 receptors respond to a totally separate group of pungent compounds, drug companies are already searching for TRPA1 antagonists that might treat chronic pain, asthma, arthritis or migraine headache, Garrity says.
The TRPA1 receptor responds to oxidative stress caused by nasty compounds called free radicals. “It is a key to many aspects of pain and inflammation,” Garrity says.
- David J. Tenenbaum