Source: Harvard Medical School/David RobersonThere’s itch, and then there’s itch.
New research led by Clifford Woolf, HMS professor of neurology, and David Roberson, HMS graduate student in neuroscience, has revealed distinct sets of itch-generating neurons that explain why current itch therapies often fail and suggest new ways to selectively silence itch.
“We think this has therapeutic implications,” says Woolf, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and a co-senior author, with Hebrew University’s Alexander Binshtok, of the paper published in Nature Neuroscience.
One day, the very sensation that sends your fingernails scrambling over your scalp may open the door to relief. Building on the science that used the heat from chili peppers to unlatch the cellular gates for a painkiller, the researchers have shown in mice that the nerve cells that cause itch also let inside their walls a lidocaine-like drug that can put out the itchy fire.
Antihistamines don’t always work on itch because most itch sensations are not caused by histamine, the substance that induces hives and other miseries. The far more prevalent eczema, atopic dermatitis, dry skin and allergic itches are spurred by other irritants, prompting specific nerve cells to send signals from the skin to the spinal cord that scream, “Scratch!”An itch-inducing substance, called a pruritogen, opens large-pore ion channels to allow entry of the sodium channel blocker QX-314. Once inside the nerve fiber, QX-314 has access to its binding site on the sodium channel and blocks conduction only in fibers activated by the pruritogen. (Source: Harvard Medical School/David Roberson)
The notion that itch is distinct from pain has been controversial until recently. In their paper, Woolf and Roberson confirmed that there are both itch- and pain-specific nerve fibers on the skin. Also, for the first time, the researchers teased out evidence that different nerve fibers sense different kinds of itch. To get there, the scientists used a tool from pain research.
Woolf came to study itch by way of the landmark work on pain that he and co-authors Binshtok and Bruce Bean, Robert Winthrop Professor of Neurobiology at HMS, published in 2007 in Nature.  They had discovered a way to deliver a derivative of the local anesthetic lidocaine into pain-sensing nerve fibers via large pores in nerve-cell membranes called ion channels. (The technology was later licensed to Endo Pharmaceuticals.)
The active agent, called QX-314, had previously failed as a drug because it is charged and can’t cross membranes and enter all neurons, the way lidocaine can numb your whole jaw at the dentist. Instead, QX-314 became a valuable laboratory tool for biophysicists interested in studying one type of neuron at a time. When introduced into cells via recording electrodes, it blocked the ion channels, which normally allow the passage of sodium into the cell. Once there, the drug inhibited all activity in the cell.
Woolf and his team found that QX-314 could block the pain nerves if combined with capsaicin, the searing ingredient in chili peppers. Capsaicin opened an ion channel called TRPV1, which had a large enough pore to allow QX-314 to selectively enter pain-sensing neurons.
“A normal drug-delivery device is some means of delivering a compound to a particular place, either orally or by injecting it or implanting it. Our breakthrough was to use biology as our drug-delivery device so the drug would be delivered to its target site only if a particular set of pores in the membrane were opened to allow the drug in,” says Woolf. “Suddenly we had a tool to ask, ‘Is itch distinct from pain?’ and then, ‘Is histamine-dependent itch distinct from other kinds of itch?’”
It turns out that histamine activates histamine receptors on neurons that are coupled to TRPV1 while other itch-inducing substances are coupled via their receptors to a different large-pore ion channel called TRPA1. The antimalarial drug chloroquine also activates TRPA1, which may explain why so many people who take the drug suffer from intolerable itch. Silencing different types of neurons with QX-314 allowed the scientists to say that histamine and chloroquine act on different sets of neurons.
Sarah Ross, assistant professor of neurobiology at the University of Pittsburgh and the Pittsburgh Center for Pain Research, says the work has answered a lingering question about itch. She was not involved in the research.
“Clifford Woolf has done it again. He has used an ingenious strategy to solve a more than 50-year-old riddle,” she says. “Through selectively silencing neurons, he has given good evidence of two distinct populations of neurons mediating two different kinds of itch. In these experiments he used a clever tool that also has great promise for selective itch treatment of just the neurons that are active.”
For their experiments, the scientists injected histamine or chloroquine into the cheeks of mice. Roberson watched hours of video, documenting instances of hind-limb scratching for itch versus forepaw swiping for pain.
“We could block the itch fibers with QX-314 without apparently blocking the pain nerve fibers,” Roberson says. “We also found we could block the histamine nerve fibers without blocking the fibers that respond to chloroquine.”
When both itch and pain nerve fibers are activated, pain will dominate simply because there are more pain fibers. But the scientists found that while pain suppresses itch, if pain is blocked, itch will surface. 
Roberson is now testing topical creams in mice, the first step in a long process that could eventually lead to clinical trials in people.
“If you have itch, a topical solution of QX-314 on your skin should go only into the nerve fibers that are causing the itch because in order to produce the itch, the itch channels have to be active,” says Woolf. “It won’t produce any local blockade of pain, but you get an itch cream that is only local and produces only a local anti-itch effect.”
While itch is more aggravating than life-threatening, Woolf and Roberson hope their work might one day ease the torment itch can cause, particularly in children.
“If you go into the pediatric immunology wards, you see little kids with their hands in mittens or sometimes tied down because they scratch themselves to a point where they damage themselves,” Woolf says.
Roberson is working on topical applications of QX-314 that potentially could reduce disease-related itch.
“We are very excited about the possibility that this discovery could one day provide long-lasting relief to people suffering from chronic itch,” Roberson says.
The study was supported by National Institutes of Health grants NS072040 and NS047710. It was funded, in part, by a research grant from Endo Pharmaceuticals, which has licensed the technology invented by Bean and Woolf.