Wasabi Pain Pathway in Worms May Lead to New Pain Meds for Humans

Scientists at Northwestern University say they have discovered how scalding heat and tissue injury activate an ancient pain receptor in simple organisms. Their study (“Activation of Planarian TRPA1 by Reactive Oxygen Species Reveals a Conserved Mechanism for Nociception”), published in Nature Neuroscience, may lead to new strategies for analgesic drug design for treating people, note the researchers.

Simple animals such as worms and insects do not suffer pain in the human sense, but they do use nociceptive receptor systems to steer away from potentially damaging conditions. Neurobiologist Marco Gallio, Ph.D., and his team report that planarian flatworms, fruit flies and humans may use a remarkably similar molecular genetic mechanism to respond to scalding heat, irritant chemicals, and tissue injury.

“Here we show that noxious heat and irritant chemicals elicit robust escape behaviors in the planarian Schmidtea mediterranea and that the conserved ion channel TRPA1 [transient receptor potential ankyrin 1] is required for these responses. TRPA1-mutant Drosophila flies are also defective in noxious-heat responses. We find that either planarian or human TRPA1 can restore noxious-heat avoidance to TRPA1-mutant Drosophila, although neither is directly activated by heat,” write the investigators.

“Instead, our data suggest that TRPA1 activation is mediated by H₂O₂ [hydrogen peroxide] and reactive oxygen species [ROS], early markers of tissue damage rapidly produced as a result of heat exposure. Together, our data reveal a core function for TRPA1 in noxious heat transduction, demonstrate its conservation from planarians to humans, and imply that animal nociceptive systems may share a common ancestry, tracing back to a progenitor that lived more than 500 million years ago.”

“[Planarians] use the same molecular receptor as flies, mice, and humans to detect potentially damaging or noxious stimuli from the environment,” said Dr. Gallio, assistant professor of neurobiology in Northwestern’s Weinberg College of Arts and Sciences and the study’s corresponding author. “Planarian flatworms are amongst the simplest animals with a central brain, and they are capable of active behaviors such as hunting and foraging. As such, they are a great model for understanding some of the basic principles of nervous system function.”

The Gallio research team found that planarians possess their own variant of an already famous receptor, TRPA1. TRPA1 is best known as the “wasabi receptor” in humans and as a sensor for environmental irritants giving rise to the sensation of pain and itch. In their study, Gallio and colleagues discovered that the simple planarian also possesses TRPA1 and that, like in humans, it controls the responses to irritant chemicals. In other ways, however, the planarian TRPA1 was more like the fruit fly’s TRPA1; rather than being activated by painful cold temperature (like the human’s), it proved essential to steer the worms away from dangerous heat.

“Planarian worms engineered to lack TRPA1 appeared completely insensitive to potentially lethal heat and ventured into our heated experimental chamber as if completely unaware of the danger,” continued Dr. Gallio. “This was remarkable but also puzzling. We knew from other experiments that planarian TRPA1 was not directly activated by hot temperature, like TRPA1s from other species are.”

To further test this, the researchers designed an ambitious experiment. “We produced gene swaps between planarian worms, humans, and flies,” explained Dr. Gallio.

“We discovered that the planarian TRPA1 (insensitive to heat, on its own) and even the human TRPA1 gene (activated by cold rather than heat) could rescue a TRPA1 mutant fruit fly and restore its ability to respond to scalding heat. This was both exciting and baffling,” he said.

The solution to this puzzle came from further experiments, showing that potentially dangerous heat causes the production of a chemical intermediate in both planarians and flies. Tissue damage is often accompanied by the rapid production of a chemical signature composed of H₂O₂ and other ROS.

“Our results demonstrate that H₂O₂ and ROS are also produced by scalding heat, and this fits well with the role of TRPA1 as a receptor for a variety of irritant chemicals, including H₂O₂ and ROS,” pointed out Dr. Gallio.

The idea that Dr. Gallio and his colleagues propose is that when an animal, be it a worm, a fly, or a human, comes in contact with potentially damaging temperatures, rapid, localized production of H₂O₂ and ROS from the scalded tissue activates TRPA1 on nociceptive neurons, contributing to the trigger of an alarm response that steers the animal away from further danger.

The team’s research with flatworms is promising, according to Dr. Gallio, because TRPA1 is a major target for new analgesic drugs.