Swiss study in mice may lead to new pain drugs

CHICAGO – Enhancing a natural pain-filtering mechanism in the spine helped relieve chronic pain in mice without the unwanted side effects of current pain relievers, Swiss researchers said on Wednesday.

They honed in on a specific molecule that helps prevent chronic pain signals from reaching the brain, without blocking normal pain messages that alert people to danger.

And they said their experiments in mice may point the way to better drugs in humans.

“Our approach addresses primarily chronic pain,” said Hanns Zeilhofer of the University of Zurich in an e-mail.

He said analgesics such as aspirin can cause stomach ulcers, while opioids such as morphine make patients sleepy and are addictive.

Zielhofer’s idea was to find a way to trick the body into intercepting pain signals before they cause havoc in the brain.

“We know that normally the spinal cord acts as filter for pain signals. It prevents most of the pain signals from reaching the brain, where pain becomes conscious,” said Zeilhofer, whose study appears in the journal Nature.

Zeilhofer’s team focused on a molecule called GABA that that can inhibit pain signals.

A class of drugs called benzodiazepines, which include diazepam — better known as Valium — bolsters the action of this GABA molecule in the central nervous system. The drugs are used to treat things like anxiety and insomnia, but when injected near the spine, these drugs also relieve pain.

“Problem is, they must not be used in chronic pain patients because of undesired effects that they have in the brain,” Zeilhofer said in an e-mail. “They make patients sleepy, they impair memory and can cause addiction.”

But benzodiazepines target at least four different GABA receptors that mediate pain control.

“These receptors turned out to be predominately present in the spinal cord and occur in the brain at much less density,” he said. By targeting just two of the GABA spinal receptors, they might be able to make a drug that could be used for chronic pain without losing potency or making people sleepy.

To test this, the researchers used genetically engineered mice to target only the GABA receptors in the spine. Then they irritated nerves in the paws of mice, making them more sensitive to touch and measured how fast the mice pulled away when gently touched.

“When we treated the mice with the right drugs, their sensitivity to this touch became normal again,” Zeilhofer said. And it worked without unwanted sedation or impaired motor function.

“Normal pain, however, was retained. This is important because normal pain has a protective function as it warns us of tissue damage,” he said.

They also used brain scans on rats to see how the drugs worked in certain pain centers that control both the sensation of pain and the feelings of anxiety that pain can produce. The scans showed the drugs reduced pain in these brain regions.

Zeilhofer said the study showed that targeting specific GABA receptors may provide a promising new target for drug development. “The next big challenge will be to develop drugs which work in humans,” he said.