Five compounds have been created that appear to control chronic pain in rats to an unprecedented degree, all based on a protein found in cone snail venom.
The announcement was made by Dr David Craik to the American Chemical Society at its conference in Dallas.
Pain is an extremely complex process, with multiple channels for transmitting pain signals. While painkillers are effective at blocking specific channels, we know very little about how to control certain sorts of pain. In particular, we are generally much better at treating acute pain caused by a sudden injury than chronic neuropathic pain from sources such as diabetes, cancer or MS. Craik noted that treatments that do exist for these sorts of pain generally only make a major difference to one in three patients and come with serious side effects.
Many of the most promising chemicals for chronic pain relief come from venomous animals. Evolution has honed the proteins in venoms to a remarkable degree, and with venoms changing much faster than the animals themselves when species become separated there are a lot of options to study. Exactly why so many of these venoms have analgesic effect is not clear – it is not as if the biters and stingers have decided to take pity on their victims by giving them an easy death. Nevertheless, the potential is enormous.
Cone snails are gastropod mollusks common on coral reefs and in tropical tidal zones. Their venom is held in a gland within a tooth which they fire at prey or enemies like a harpoon. The smaller species produce a painful sting like a bee, but larger ones can be fatal.
In their raw form conotoxins are broken down by the body's enzymes and therefore cannot be taken orally. Ziconotide is the first painkiller based on cone snail toxins, but Craik says it needs to be injected directly into the lower spinal cord, greatly limiting its application. However, by modifying some of the cone snail's proteins to form a loop of amino acids Craik has made them far more stable.
Although they have yet to be tried on humans, these modified peptides (small proteins) appear to dramatically reduce pain response in rats, even when given in very small doses. Craik estimates the effect is 100 times as large as morphine or gabaentin, the benchmark pain relief drugs. Since the cone-based drugs target different receptors to opiates it is thought unlikely they would produce the same addiction response.
“We don’t know about side effects yet, as it hasn’t been tested in humans. But we think it would be safe,”, Craik said.
A few days after the talk Craik's colleagues at the University of Queensland revealed in Nature Communications that cone snails use different venoms for hunting prey and defending themselves against predators. “Most venomous animals are thought to inject the same combination of venom toxins for both hunting prey and defending themselves from predators,” said Professor Richard Lewis.
“We found that the geography cone [Conus geographus] only injects this lethal venom when it feels threatened and acts in defense,” Lewis said. “However, when hunting prey such as fish, they inject a less powerful and complex venom that isn’t toxic to humans, effectively switching weapons to match the situation.”
Craik identified the way small cone snail venom proteins inhibit pain sensors in the Journal of Neuroscience in 2008. He predicted at the time that these proteins might eventually be used to control chronic pain, but the path to drug development in an area like this is usually slow and winding. Nor is that path near completion. Craik thinks human trials are two years away, making widespread use a long term prospect.