Researchers identify brain areas activated by itch-relieving drug

Areas of the brain that respond to reward and pleasure are linked to the ability of the drug butorphanol to relieve itch, according to new research led by Gil Yosipovitch, professor and chair of dermatology at Temple’s School of Medicine and director of the Temple Itch Center.

The study, published online September 11 in the Journal of Investigative Dermatology, is the first to show precisely where in the brain butorphanol works to relieve itch and explain why it works better for chronic itching mediated by histamine, a small molecule involved in allergic reactions, than for non-histamine-related types of itch. The findings potentially open up new avenues to the development of chronic-itch treatments.

“The research allows us to assess butorphanol’s effects,” Yosipovitch said. “We can now identify better targets in the brain that drugs can work on to relieve itch.”

Yosipovitch explained that chronic itching, which affects roughly 12 percent of the population, is caused by not just one disease but many—ranging from atopic eczema and psoriasis to systemic diseases such as lymphoma and chronic liver failure. Biochemically, each of those diseases induces itching via one of two main pathways: one mediated by histamine and one that is not. Most pathological itching originates along non-histaminergic pathways.

The researchers experimentally induced itch in human volunteers using either histamine or cowhage, which incites non-histaminergic itching. The volunteers were then treated with either butorphanol or a placebo and subjected to functional magnetic resonance imaging (fMRI) to analyze brain activity and assess the effects of butorphanol. Seven days later, they received the other treatment and again underwent fMRI.

Butorphanol suppressed histamine itching in all cases and reduced cowhage (non-histaminergic) itching in 35 percent of subjects. The drug’s suppression of histamine itching was associated specifically with the activation of brain areas located deep at the base of the forebrain that are notably rich in so-called kappa (κ)-opioid receptors, on which butorphanol acts. By contrast, the relief of cowhage itch by butorphanol was linked to effects in other brain areas.

The findings suggest that butorphanol works primarily on κ-opioid receptors to suppress the itch sensation induced by histamine. But the drug also has important effects on an itch pathway that does not involve histamine, where the demand for new treatments is greatest.

The new study, which Yosipovitch carried out at Wake Forest University prior to joining the Temple School of Medicine faculty in 2013, also further illustrates the power of applying imaging technologies to basic questions in itch research. At Temple’s Itch Center, Yosipovitch continues to explore those applications.

“We are in a position now to better understand the itch-scratch cycle,” he said. “To break the cycle from the top down, knowing where to target receptors in the brain, would be a major achievement.”

Researchers from Wake Forest University and Virginia Tech collaborated in the study, which was supported by a grant from the National Institutes of Health.

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