A toxin derived from the skin of a South American frog has led to a potential new painkiller that may lack some of morphine's side-effects. In animal tests, the drug, which apparently acts not through opioid receptors, but instead through a receptor for the neurotransmitter acetylcholine, has proved effective in blocking both acute and chronic pain. What's more, researchers have seen few signs that the drug, reported in today's Science, is addictive or toxic.
The drug's design was based on a compound extracted from the skin of an Ecuadorian frog by chemist John Daly, of the National Institute of Diabetes and Digestive and Kidney Diseases. In 1976, he discovered that the compound, called epibatidine, is 200 times more potent than morphine at blocking pain in mice. Unfortunately, it also caused seizures and even death. About 10 years later, his lab used nuclear magnetic resonance spectroscopy to determine that epibatidine's structure resembles that of nicotine. Other experiments showed that the compound activates the nicotinic acetylcholine receptor.
The research caught the attention of a team at Abbott Laboratories in Abbott Park, Illinois, which noticed that epibatidine's structure resembles that of compounds they were studying as Alzheimer's therapies. Neuropharmacologist Stephen Arneric and his colleagues fiddled with their compounds, trying to create a derivative that exclusively kills pain.
They have now shown that one variant, called ABT-594, is as effective as morphine in dampening acute and chronic pain in rats. By placing electrodes in the spinal cords of rats, the researchers also showed that the drug hinders the ability of nerve cells to fire in response to harmful mechanical and thermal stimuli, but it does not affect responses to touch or mild heat. The company also found, Arneric says, that ABT-594 depresses the respiratory system much less than morphine does, and it makes animals more alert instead of sedating them. Also, in at least one test, ABT-594 appeared to be nonaddictive.
Much more work will be needed to determine whether the drug is safe and effective in humans. For example, other researchers point out that ABT-594's mechanism of action raises the possibility that it will lead to other forms of dependency. Abbott has already started safety trials in Europe and hopes to conduct trials in this country as well. "If it works in people, it's going to be a completely new kind of pain reliever," says Howard Fields, professor of physiology and neurology at the University of California, San Francisco.