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Drug dials down intense opioid-related itching

Chronic itching is a common side effect of opioids—a problem for some people who need the drugs for pain relief and for others fighting addiction.

A new study with mice finds a drug delivers itch relief by targeting particular opioid receptors on neurons in the spinal cord. Nalfurafine hydrochloride (brand name Remitch) is approved in Japan to alleviate itching in dialysis patients with chronic kidney disease and in patients with severe liver disease.

The drug is also being tested for its anti-itch effects in the United States, but until now scientists didn’t understood how it works.

As reported in Cell Reports, the drug targets what’s known as kappa opioid receptors on neurons in the spinal cord and may be effective against many types of chronic itching that don’t respond to conventional drugs such as antihistamines.

While other opioid receptors on the same neurons can ramp up itching, this study shows that activating the kappa receptor significantly dials it down.

“The kappa opioid receptors activate a pathway that tamps down the activity of GRPR, which our lab previously identified as the first itch gene,” says senior investigator Zhou-Feng Chen, professor of anesthesiology and director of the Center for the Study of Itch at Washington University School of Medicine in St. Louis. “This gene relays itch signals from the spine to the brain.”

Chen and colleagues studied mice treated with a substance to make them feel itchy. Others had been genetically engineered to develop chronic itching. When the drug was injected directly into the spinal cords of the animals, their scratching was markedly reduced.

About half of the neurons in the spinal cord that transmit itch signals were found to have kappa opioid receptors, and when those receptors are activated, they inhibit GRPR.

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It may not be practical to administer spinal cord injections of drugs to patients with chronic itch—whatever the cause—but now that a way to alleviate such itching has been identified, researchers can try to activate the same receptor in other ways.

Or, Chen says, they may target some of the downstream molecules that are activated when the kappa receptor is targeted.

“Some molecules downstream from the kappa receptor may still be able to tamp down itching without causing any unwanted side effects that may occur when drugs activate the kappa receptor in parts of the body outside of the spinal cord,” says Chen, who also is a professor of psychiatry and of developmental biology.

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His team is now working to learn whether those strategies will work in mice, with the hope that the same molecules eventually may become therapeutic targets in people with chronic itch.

The National Institutes of Health and the National Natural Science Foundation of China funded the work.

Source: Washington University in St. Louis

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