WIKIMEDIA COMMONS, LA DAWSON/AUSTIN REPTILE SERVICE
The Texas coral snake's bite rarely kills, but it can cause intense, persistent pain. Delving into the mechanism underlying the reptile's vicious venom, researchers have discovered two chemicals that combine and stimulate ion channels previously thought to respond mainly to acid levels, according to a paper published today (November 16) in Nature.
“It’s a new paradigm in thinking,” said neuroscientist Kenton Swartz of the National Institute of Neurological Disorders and Stroke, who was not involved in the study. “There are all these interesting ion channel toxins in venom, but in this case it’s two different molecules that have to interact with each other first before they can alter the ion channel.” By studying the venom and how its toxins mediate pain pathways in the snakes’ victims, researchers may be able to gain new insights into pain perception and possible targets for pain management.
Researchers are interested in teasing out how natural toxins work because they often reveal hidden biological pathways for sensing pain, activating nerves, or regulating heart function, which can lead to new ways to blunt pain, said David Julius, a neuroscientist at the University of California, San Francisco.
Julius and his team decided to test snake venoms because of their particularly intense pain response. The team applied samples of several different venoms to mouse neurons and measured how strongly the nerves fired as a result. The most robust response came from the venom of the Texas coral snake, a shy but potentially dangerous snake that lives in forested areas of the southern United States.
Testing the activity of each chemical in the venom, the researchers found that no single chemical on its own caused a response. Slightly stumped, the researchers “took the leap of faith that maybe there’s two components in the venom that act together,” Swartz said. Sure enough, the team found two compounds that formed a complex, which in turn elicited neuronal firing.
The team added the complex to sensory neurons and measured the flow of ions through different channels on the membrane. The toxins caused ions to flow through acid-sensing channels, which, as their name suggests, open or close in response to the pH of the cellular environment. While acid-sensing channels have previously been tied to pain caused by oxygen deprivation in heart tissue, no one had shown that the channels played such a key role in broader pain response before, Julius said.
To confirm that the involvement of the acid-sensing channels in pain in live organisms, the researchers injected the snake toxin into the paws of mice, and the paws shook in pain. Mice engineered to lack this channel, on the other hand, showed no evidence of being in pain, providing “strong evidence for the role of this channel in pain pathways,” Swartz said.
The results could be used to develop new pain medicines, by blocking acid sensing channels or interfering with other chemicals that may activate them, he added. “Any identification of molecules in new pain pathways opens up the possibility of developing drugs that target them as pain therapies.”