Scratching the surface

BY Jim Dryden

As native St. Louisan and baseball philosopher Yogi Berra once said: “You can observe a lot just by watching.” Although he never heard Berra’s famous “Yogi-isms” while growing up in China, Zhou-Feng Chen, PhD, has followed the former catcher’s sage advice anyway.

Chen decided that if he wanted to learn whether an animal is itchy, an easy way to find out would be to watch and see whether the animal scratches. So for the last couple of years, Chen and others in his laboratory have spent a good deal of time watching mice scratch.

It all began when Chen, an associate professor of anesthesiology, psychiatry and developmental biology was trying to learn more about pain sensation. His laboratory was looking for genes in the spinal cord that might be related to the pain response. Itch also was involved because historically, scientists had thought of the itch response as being a slightly less intense version of pain and that both sensations were transmitted through the same neural pathway.

That’s what it said in the neurology textbooks, anyway. As it turns out, those text-books were wrong.

While searching for genes related to pain, Chen’s lab began studying a gene called GRPR (gastrin-releasing peptide receptor). Among the potential pain-sensing genes they identified, GRPR stood out because it was active on a relatively small number of nerve cells in the spinal cord.

To get an idea of what the gene was doing, they studied mice without the GRPR gene to learn how they were different from normal animals.

“At first, we were a little bit disappointed,” Chen says, “because the mice without a GRPR gene seemed to react to painful stimuli in the same way normal mice did.”

But then they injected the normal mice with a substance that stimulates GRPR, and the mice started to scratch.

“That’s when we thought the gene might be related to itch sensation,” Chen says. “So we began to look carefully at the itch response in mice with and without GRPR.”

They studied itching by watching the mice scratch, and the researchers found that the normal mice scratched vigorously when exposed to a variety of itch-producing substances. The mice without GRPR, on the other hand, scratched less.

But when either strain of mouse was exposed to painful stimuli, such as an injection, the mice without GRPR withdrew and licked themselves just like the normal mice.

So, although they reacted very differently to itchy things, they both avoided pain and reacted to painful stimuli in identical ways. From that behavior, Chen was able to recognize that pain and itch were not two parts of the same response, but were different responses altogether.

This told the researchers that GRPR was helping to regulate itch and, because the gene was functional only on a small number of neurons, Chen’s team zeroed in on those particular cells to see whether they made up an itch-specific pathway in the spinal cord.

In the September 18, 2009 issue of the journal Science, Chen reported that such a pathway was likely. Unlike the earlier experiments involving mice without GRPR, this time Chen’s team injected the spinal cords of normal mice with a neurotoxin called bombesin-saporin. The neurotoxin binds to GRPR, and it killed the neurons that had a functional GRPR gene.

Then they looked at the mouse behavior again. When the mice injected with bombesin-saporin were exposed to things that caused itching, they didn’t scratch. An appropriate dose of the neurotoxin caused the mice to scratch 80 percent less and, in some cases, eliminated scratching altogether.

Further tests on the mice showed that other neurologic functions, such as motor control, were not affected when GRPR-expressing neurons were destroyed. But, as with the mice without GRPR, the pain response wasn’t affected. “This finding has very important implications for therapy,” says Chen, who also is an investigator at Washington University’s Pain Center. “We’ve demonstrated that GRPR functions on specific neurons that are critical for itching, but not for pain.”

The ability to separate pain sensation from itch suggests that it may be possible to treat itch with drugs that don’t alter the pain response, and vice versa. That’s important because pain can be an important protective cue that warns of danger, says Alex S. Evers, MD, the Henry E. Mallinckrodt Professor and head of the Department of Anesthesiology. “This means that potentially we can design agents that selectively block out the pruritic side effects of pain-killing drugs, particularly opiates,” says Evers. “This could be important in allowing better analgesic therapy in a variety of situations from cancer pain to la-bor pain.”

Itching is a common side effect of painkillers like morphine, and treatment options for itchy patients have been limited. But Chen’s team already has decoupled itching induced by opiates from pain control in mice.

“If we inject a GRPR inhibitor and morphine into the spinal cord in the mouse, the drug continues to have its analgesic effect, but the mice don’t scratch,” Chen says. “That provides still more evidence that analgesia and itching can be separated.”

Many human patients with chronic pain receive spinal perfusions of opioid drugs to control their pain. Perhaps, Chen says, one day those patients may receive the opioid drug along with a second drug that inhibits GRPR so that they can enjoy the benefit of pain relief without the side effect of itching.

Chen is now working to characterize the itch-specific neuronal pathway. He’s also studying GRPR-expressing neurons in the spinal cord, looking for other genes that may be related to the itch response. Meanwhile, he continues to keep an eye on his mice because, after all, you really can observe a lot just by watching.

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