Placing a Chinese red headed centipede on a burn can speed up the healing process, according to ancient Chinese medicine. But a mouse study published today suggests that what the Chinese interpreted as a healing effect may in fact have been the handiwork of a pain-inhibiting peptide contained within this centipede’s venom, which kills insects but is harmless in humans. The results indicate that the peptide, called m-SLPTX-Ssm6a, is a powerful analgesic that, in some cases, surpasses the effect of morphine. Given its apparent lack of side effects, Ssm6a is seen by scientists as an attractive candidate drug compound that might prove suitable for treating chronic pain.
Researchers first discovered Ss6ma’s effect by screening it, and other peptides, for the ability to inhibit Nav 1.7, a channel located on the surface of nerve cells that allows sodium to transmit pain signals when the cell membrane is depolarized. Nav 1.7’s importance in pain signaling came to light in 2006 when researchers linked mutations in the channel to a rare genetic condition in which people are unable to perceive pain. The finding led many researchers to suggest developing pain medications composed of small molecules that could block the channel.
But there was a problem with this approach: Nav 1.7 is one of nine types of so-called ‘voltage-gated sodium channels’, all endowed with similar channel entrances that, if blocked all at once, would lead to major neurological malfunctions including cardiac arrest. “This makes it really hard to get selectivity,” explains Glenn King, a structural biologist of the University of Queensland, Australia, and a co-author of the study, which appears in the Proceedings of the National Academy of Sciences. Luckily, he says, “toxins found in venoms are much bigger,” so their action does not take place at the channel entrance.
This property plays a central role in Ss6ma’s effectiveness, because rather than binding to the channel’s pore, “it prevents Nav 1.7 from turning on and opening up,” King says, by interacting with areas of the channel that are sensitive to charge, thus increasing the voltage needed to activate Nav 1.7. According to King, Ss6ma is the most selective Nav 1.7 inhibitor reported to date.
In the study, mice that received injections of the peptide were able to withstand heat applied to their tails for 13.4 seconds, on average; their control counterparts could only stand the discomfort for 5 seconds before pulling away. Additionally, in a part of the experiment in which the mice received painful stimuli to the paw, Ss6ma reduced paw licking, a measure of pain, by 80% compared with 57% for those given morphine.
“The inhibition of Nav 1.7 is real,” says Mandë Holford, a chemical biologist at Hunter College in New York who was not associated with the study. For Holford, the discovery of Ssm6a is especially noteworthy because “it comes from an organism not usually associated with drug discovery.”
The researchers found no side effects for Ss6ma in the treated mice, even when they increased the dose to ten times what was needed to inhibit pain. This means that, contrary to morphine, whose effect on opioid receptors wanes over time, Ss6ma might not cause tolerance and addiction. Moreover, the peptide degraded slowly in human plasma and simulated gastric fluid, indicating that an eventual human drug could be stable enough to be administered on a weekly, rather than daily, basis.
The issue that worries King most—other than the basic question of human tolerance of Ss6ma—is “the rate at which the [human] kidney will clear the molecule.” And because the compound seems to block all pain perception, “it could be dangerous to give this to a small child who might not notice other injuries,” he adds, noting that the centipede-derived toxin might be best suited for development to treat adult sufferers of chronic pain.
Image by Yasunori Koide via Wikimedia Commons