Brain regions tied to reward and pleasure are linked to the ability of the drug butorphanol to relieve itch, new research led by Gil Yosipovitch, MD, Professor and Chairman of the Department of Dermatology at Temple University School of Medicine and Director of the Temple Itch Center, finds. The study implicates opioid receptors in the brain—known for their role in pain, reward and addiction—in the suppression of itch, offering potential directions for new treatments for chronic itch.
The study, published online September 11 in the Journal of Investigative Dermatology, is the first to map where butorphanol acts in the human brain to reduce itch. By pinpointing the precise brain areas involved, the research helps explain why butorphanol is more effective against histamine-mediated itch than against non-histamine itch, and it highlights brain targets for future itch-specific therapies.
According to Dr. Yosipovitch, “This research allows us to assess butorphanol’s effects more accurately. We can now identify better targets in the brain that drugs can act on to relieve itch.”
The work advances the search for treatments tailored specifically to chronic itch, a symptom that affects roughly 12 percent of the population and arises from many different conditions. Chronic itch is not a single disease but occurs across a spectrum of disorders—from atopic eczema and psoriasis to systemic illnesses such as lymphoma and chronic liver disease. Biochemically, these conditions produce itch through two major pathways: histaminergic (mediated by histamine) and non-histaminergic. Most pathological itching arises from non-histaminergic pathways, where effective therapies are most needed.
In collaboration with Alexandru D. P. Papoiu, MD, PhD, at Wake Forest University School of Medicine, Dr. Yosipovitch induced itch in healthy volunteers using two methods: topical histamine to trigger histaminergic itch, and cowhage to provoke non-histaminergic itch. Volunteers received either butorphanol or a placebo and then underwent functional magnetic resonance imaging (fMRI) to record brain activity while reporting itch intensity. When participants returned seven days later, they received the alternate treatment and were scanned again, enabling within-subject comparison of butorphanol versus placebo effects on both histamine and cowhage-induced itch.
Study results showed that butorphanol abolished histamine itch in all participants and decreased cowhage itch in about 35 percent of subjects. Relief of histamine-induced itch was specifically associated with activation of the nucleus accumbens and septal nuclei—deep basal forebrain structures that contain high levels of kappa-opioid receptors. These receptors are known targets of butorphanol, suggesting a primary mechanism by which the drug suppresses histaminergic itch. The partial relief observed for cowhage-induced, non-histaminergic itch was linked to alterations in other brain regions, indicating that distinct neural circuits mediate different types of itch and respond differently to opioid modulation.
While the findings support a key role for κ-opioid receptors in suppressing histamine-related itch, the way opioid receptors reduce non-histaminergic itch remains less clear. Opioid receptors modulate the transmission of itch-related signals in the brain and are abundant within neural circuits associated with reward and pleasure. Prior work by Drs. Yosipovitch and Papoiu has shown that activation of reward circuits correlates with the pleasure of scratching and with the degree of itch relief obtained from self-scratching. The current pharmacological fMRI study reinforces those connections and demonstrates how imaging can reveal neural targets for anti-itch therapies.
Dr. Yosipovitch conducted this study at Wake Forest University before joining the faculty at Temple University School of Medicine in 2013, and he continues to pursue brain-based itch research at the Temple Itch Center. “We are in a position now to better understand the itch–scratch cycle,” he said. “Breaking that cycle from the top down, by targeting receptors in the brain, would represent a major therapeutic advance.”
Other contributors to the research include Robert C. Coghill, Department of Neurobiology & Anatomy, Center for Integrative Medicine, Wake Forest University School of Medicine; and Robert A. Kraft, Department of Biomedical Engineering, Virginia Polytechnic Institute & Wake Forest University, Winston-Salem, NC.
The research was supported by NIH grant number R01AR055902.
Contact: Gil Yosipovitch, Temple University School of Medicine.
Source: Temple University School of Medicine press release.
Image Source: Image credited to Orrling and Tomer S. Licensed Creative Commons Attribution-ShareAlike 3.0 Unported.
Original Research: Papoiu ADP, Kraft RA, Coghill RC, Yosipovitch G. “Butorphanol Suppression of Histamine Itch is Mediated by Nucleus Accumbens and Septal Nuclei. A Pharmacological fMRI Study.” Journal of Investigative Dermatology. Published online September 11, 2014. DOI: 10.1038/jid.2014.398.