Suffer the little amphibians

Is it any kinder to experiment on frogs than mammals? Julia Hinde meets one American scientist who believes so

Does a frog feel pain? That is the question underpinning the pioneering work of one US scientist, whose research could end years of conflict between scientists and animal-rights activists.

Craig W. Stevens, associate professor of pharmacology at the Oklahoma State University College of Osteopathic Medicine is using North America's most common frog, the northern grass frog, Rana pipiens, instead of the more commonly used, and cuddlier, cats, dogs and monkeys, to test new painkilling drugs.

Research into pain, by its very nature, involves suffering. Scientists claim that 95 per cent of research animals are drugged if there is any chance of their being hurt, but research into pain inevitably means hurting an animal. Only after a pain threshold is established can the experiment be repeated with a painkilling drug, to establish the drug's effectiveness.

Stevens says his decision eight years ago to adopt amphibians rather than mammals to test new drugs was an ethical one. He believes we will never know for certain whether or not animals can feel pain, by which he means the complex emotional sensation felt by humans.

"We do not have the ability to detect conscious experiences such as pain in animals. To think otherwise is not science, but science fiction," he says. "But even if we cannot say for sure whether there is a capacity for pain, if the capacity for pain does exist in animals, it is likely to be less in early-evolved amphibians than in mammals. All brains are not created equal."

But are not frogs a million miles from mammals and humans? Is the model scientifically appropriate? Stevens thinks so. Drugs that work on people, such as the analgesics codeine and morphine, appear also to work on frogs, while the simplicity of a frog's brain offers considerable scientific benefits.

Pain research in the US is coming under increasing scrutiny, although US animal researchers, Stevens believes, rarely suffer anything like the attention or threats experienced by their British scientific counterparts.

Stevens adds that alongside the ethical considerations, economic and practical factors are also important. For the cost of keeping and experimenting on one rat, Stevens can afford six frogs - an important consideration in cash-strapped universities. He adds that the traditional field was saturated with young researchers. There is something exciting about being the pioneer in a new field. "I didn't want to carry on using mammals as I did for my PhD. I was not sure that the rat model was the best possible, and I didn't like getting bitten."

However, researchers at the Oklahoma laboratory did find one important difference between human and frog responses to pain. Drugs produce analgesia by binding with specific proteins in neurons called opioid receptors. In mammals - including humans - there are known to be three types of opioid receptors, each capable of binding with only one type of opioid drug. However, in frogs, this does not appear to be the case. The group believes that in frogs there is just one type of opioid receptor, which they call the unireceptor, capable of binding all three types of opioid agents. "Perhaps there has been gene duplication and divergence so that ancestral opioid receptors in an early evolved vertebrate might have diverged to become separate sites in mammals," suggests Stevens. He says the idea of a unireceptor in frogs - if it is confirmed by future studies - may lead to a better understanding of the human pain system and why it has evolved to have three separate opioid receptors instead of just one.

Despite the apparent benefits of Stevens's research and the mandate championed by the US government supporting the "refinement, reduction and replacement" of existing animal models, funding has been a problem. "Most US funding mechanisms tend to be fairly conservative," Stevens says. "If it is not a well-established model, federal sources, such as the National Institutes of Health, are not likely to fund it. They almost always want a guaranteed project so that they do not have to take too many risks and creative leaps. That is one reason people keep away from developing alternative models."

He adds that he has had similarly little luck with the so-called alternative foundations, because he still uses whole animals, rather than doing in vitro work. "It is frustrating," he says. "I am stuck in the middle. But we believe the amphibian model really does provide a unique opportunity."