Sea Snail Venom could be ‘The Holy Grail’ in Pain Therapeutics

Australian scientists are one step closer to developing new pain relief drugs from the chemicals used by venomous sea snails.

The chemicals are known as conotoxins and up until now it has been hard to administer the right dose without causing bad side effects.

But researchers working across three different Australian universities say they have made a breakthrough that could make it safer to use the toxins.

It is hoped the drugs will eventually reduce reliance on highly addictive opioid-based painkillers and provide effective relief for the one in five Australians affected by chronic pain.

Macdonald Christie, a professor of pharmacology at the University of Sydney, has been looking into the use of conotoxins as part of a study funded by the National Health and Medical Research Council.

“Early indications are that conotoxins are more effective than both opioids and cannabinoids, may have fewer side effects, and the additional benefit of treating the cause of pain,” he said.

Research has found that conotoxins appear to provide long-lasting pain relief through a range of mechanisms, such as blocking the pain signal through the nervous system.

“Unlike the classical drugs that we use — opiates, local anaesthetics that shut down all nerve activity — we’re looking for very specific targets,” Professor Christie said.

“And that’s really the holy grail of development of new pain therapeutics, because the drugs that we have at the moment don’t work well for many people.”

What are conotoxins?

Venomous sea snails use conotoxins to immobilise and kill their prey.

“This is a snail that can drop a fish in less than a second. And then they ingest the fish,” Professor Christie said.

“So we understood a long time ago they must be shutting down the nervous system of the fish.

“And we now know that they have thousands upon thousands of molecules in their venom that have learnt over evolution to inactivate the nervous system of fish.”

Cone snailInternational research into conotoxins has been underway for decades and currently includes teams from the University of Queensland, the University of Melbourne, the South Australian Health and Medical Research Institute, and the University of Utah Health.

The current conotoxin therapeutic in clinical use, Prialt, is a powerful painkiller sometimes used by people when morphine no longer works.

However it is difficult to administer the correct dose without inducing bad side effects.

Professor Christie said that was because its toxicity was about the same dose as the dose that relieves the pain, making it difficult to adjust the dose based on a patient’s response.

Another problem with Prialt is that because it does not cross the blood-brain barrier it has to be applied to the spinal cord by an infusion pump.

The blood-brain barrier is a type of membrane preventing most compounds in the blood from entering the brain, and without access to the brain the drug cannot ease pain.

But the conotoxins now in development would hopefully be administered orally.

Potential for conotoxin to ‘reverse damage’

A huge benefit of the conotoxins currently being studied is that they appear to be less addictive than any opioid-based pain killers.

“One of the big problems with opiates is they cause tolerance, so in severe chronic pain patients the dose needs to go up and up and ultimately become completely intolerable,” he said.

“And [patients] also have a high risk of overdose.

“We know that tolerance doesn’t develop to the conotoxins that we’re working on — and there are many different classes of conotoxins.

“So we’ve got many therapeutic opportunities to what is the holy grail for pharmacology of pain therapeutics in finding new and novel targets.”

Professor Christie’s team also discovered conotoxins appeared to reduce the inflammation at the sites of nerve injuries, as well as possibly having a curative effect.

“Most of the drugs that we use to control pain don’t actually reduce the underlying pathology, they only treat the symptoms — in effect they shut the nerves down or they reduce nerve transmission,” he said.

“Some of the conotoxin we’re looking at actually seemed to reverse damage to some extent.”

The big breakthrough

For a long time pharmacologists have generally believed that the most powerful conotoxins worked best.

However Professor Christie and his team have discovered that some of the less potent kind of toxins that did not stick to their target in the nervous system as effectively were much safer.

Those less potent toxins neutralised the nerves and then moved away, having less impact on the nervous system and thus lowering the side effects.

“So the initial ones in use, as soon as they travel anywhere in the nervous system — which eventually they do — they block up those parts of the nervous system and cause terrible side effects,” he said.

Side effects include hallucinations, delusions, the inability to move properly and complete confusion.

“So memory disruption — so they’re not very well tolerated,” Professor Christie said.

“If we can get them to be more safe and effective then we’re in a much better position.”

Professor Christie said he was hopeful conotoxins would be in clinical use in less than 10 years, “provided further money is available for trials”.

“The conotoxins that we’re working on, we have intellectual property protection on most of them, we’re looking for commercial partners to develop those,” he said.

Source