What will ease the pain? Ask a frog.

It's hard to do pain research without causing a little, well, pain--or at least what passes for it. Moreover, because "cells don't feel pain," such studies must be conducted in whole animals, explains Craig W. Stevens, a pharmacologist at the Oklahoma State University College of Osteopathic Medicine in Tulsa. With the aim of finding test subjects that feel less discomfort, he's leaped into research on what he believes is the first nonmammal "guinea pig" for analgesia, the leopard frog.

Unlike vision, "pain is more than a pure sensory perception," he says. At least in humans, he notes, it can evoke all sorts of ancillary responses, including emotions. Such responses trace to parts of the brain not found in critters from earlier in evolutionary history, such as amphibians. So, reasons Stevens, frogs' capacity for pain is probably smaller than mammals'.

For his studies, he places a drop of vinegar on a frog's thigh and watches for a characteristic wiping response, indicating irritation. If it doesn't occur, he places two drops on the opposite thigh. He keeps switching legs and upping the dose until the frog attempts to wipe the vinegar off. Then he delivers an analgesic drug to the animal and runs this acid test again.

In contrast to humans, who have three types of brain receptors for pain-inhibiting opiate drugs, frogs possess just one. Yet "the amazing thing," Stevens finds, is that the frog's receptor responds to analgesic drugs that work on any of the three human receptors. Also, relative potency of analgesics in frogs matches that in mammals. He concludes that the frog's receptor must be ancestral to the trio of receptors in mammals and that studies with these amphibians "eventually will lead to a better understanding of the molecular mechanisms of how opiates work."