University of Pittsburgh Pain Center helps explain itching

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The mere mention of itching can make it happen, triggering an urge to scratch. But more serious itching can be chronic and debilitating, with few treatments available.

The problem is, science lacks knowledge of the neural highways of itching, skin to brain.

But now the University of Pittsburgh Pain Center has made important discoveries concerning that itch pathway, from the site of the mosquito bite, brush with poison ivy, or eczema breakout, to the spinal cord.

Among Pitt’s discoveries is a key opiate-producing neuron whose existence every human should celebrate.

“You’d think we would know by now which neurons convey itch from the skin to the brain but we don’t,” said Sarah E. Ross, the physiologist at the Pitt Pain Center who led the study. “There’s a lot more to do but this is an important piece of the puzzle.”

The study was published online this month in the journal Neuron.

In the spinal cord, the study found, the body takes surprising action to control itching. There the team identified the B5-I neuron, whose production of the opiate, dynorphin, inhibits itching by at least partially blocking the neural signal traveling from the itch site to the brain.

The study also identifies a receptor protein on the surface of neurons (nerve cells) to which the dynorphin attaches and sets off the process to quell itching.

Researchers injected the antimalarial drug chloroquine into the cheeks of mice to cause itching. At the same time, they blocked the effects of dynorphin in the spinal cord. The mice scratched incessantly, in contrast to those mice that received the injection but didn’t have dynorphin blocked.

The study revealed that menthol and capsaicin (the substance that makes jalapeno peppers hot) activate sensory neurons in the skin that target B5-I neurons. That, in turn, helps explain why ice, cool, menthol and capsaicin inhibit itch: They stimulate the B5-I neurons to release dynorphin. The B5-I neuron’s role was confirmed when menthol was not able to suppress itching in mice that lack B5-I neurons.

“These investigators characterize a population of spinal inhibitory neurons and demonstrate that dynorphin, released from these neurons, is a back-scratcher responsible for modulating itch,“ stated Ethan A. Lerner and Paul Juliana Seadi Pereira, whose commentary on the Pitt study was published in the same issue of Neuron.

"Scientific investigations can be likened to scratch tickets. While individual experiments that we perform may not pan out, the [Pitt-based] study .... in this issue of Neuron is a winner,” they stated.

Pain and itch opiates

Dynorphin, a “kappa opioid,” differs from the “mu opioids” such as morphine and heroin, which reduce pain but also can induce itching. The Pitt team’s explanation of how synthetic kappa opioids inhibit itching raises hope that it can serve as a model for new itch treatments.

Dr. Lerner, a Boston dermatologist at the Massachusetts General Hospital, and Ms. Ross said pharmaceutical companies began developing kappa-opioid medications after its discovery. It initially was thought that kappa opioids could be a potential new pain remedy. But now it is emerging that the kappa class of opioids has an impact on itching with little effect on pain.

In Japan, uremic pruritus, which is an itching condition from kidney disease, is treated with the drug nalfurafine, a synthetic kappa opioid. The drug isn’t available in the United States but the U.S. Food and Drug Administration has approved an upcoming clinical trial to test its effect on uremic pruritus.

Based on her team’s research, Ms. Ross, who holds a doctoral degree in physiology, said kappa opioids or synthetic dynorphin, in theory, ”could reduce almost any type of itch,“ and emerge as an important treatment.

"Serious chronic itching is a problem that is debilitating,” she said. “It keeps people up at night and ruins their sleep. It’s a quality-of-life issue for them.” Scratching can lead to superficial skin damage and possible infection.

The study states that “one reason that itch has lagged behind pain in terms of effective therapies is because, until recently, we lacked a clear understanding of how itch is detected and encoded in the nervous system.”

But Dr. Lerner said the Pitt study adds to the substantial progress researchers have made in itch research in recent years.

“Itch, like pain, is an adverse sensation that warns us of potential threats to the body,” the Pitt study states. “However, itch is a distinct sensation, characterized by the desire to scratch. Although scratching may remove irritants from the skin (providing at least transient relief from itch), it has the paradoxical effect of causing tissue damage that potentiates itch through release of inflammatory mediators. This pathological itch-scratch-itch cycle is a hallmark of chronic pruritus, which can be just as debilitating as chronic pain.”

Two types of itch

Most over-the-counter medications for itch are antihistamines that work against histamine itching, best characterized by hives. Most chronic itching, however, is not related to histamines -- such as that related to diabetes, kidney or liver disease, eczema, some types of psoriasis, dermatitis, and the autoimmune skin disorder, pemphigus. Mosquitoes and poison ivy also are nonhistamine itches.

The study recognizes ”a great need for better therapies to treat intractable pruritus,“ or chronic itching.

But even if kappa opioids work to reduce itching, they likely won’t eliminate it.

Ms. Ross said our skin and spinal cords have redundant neural pathways, possibly involving other excitatory neurons that help signal the brain to prompt scratching. That would explain why dynorphin reduces but doesn’t eliminate itching.

Other recent studies, she said, have identified three neurons potentially involved in such redundant pathways, including a sensory neuron in the skin that signals excitable, itch-producing neurons in the spinal cord, which in turn signal the brain. Other neurons could be involved, as well.

"We know that there are projection neurons which convey itch information from the spinal cord to the brain, but we don’t know which ones they are and we don’t know whether they are truly selective for itch, or whether they convey both itch and pain.” Ms. Ross said. recommends taking good care of one’s skin by using moisturizers for dry skin and sunscreens. Use mild soap and bathe in warm, rather than hot, water. It also recommends avoiding such fabrics as wool and certain synthetic fibers, which can cause itching. Cotton clothes and bed sheets are recommended. Cooler temperatures in the house along with a humidifier also can help reduce itching.

And, rather than scratch, use ice or a cool washcloth to quell the sensation.

New research topics include the relationship between pain and itching and whether they share or have separate pathways to the brain. It’s clear with itching that nothing occurs in isolation.

”Therefore, there are multiple ways to block itch but multiple ways for itch or pain to still occur,“ Dr. Lerner said. ”So one of the things we marvel at and are confused with is, why are there so many redundancies in the system? Why does the body make it so hard to interrupt the pathways and sensations? I can’t imagine why itching is so important to us.“

The Pitt research, he said. reveals a rare example of turning down the volume or activation of a cell. Usually research works to figure out ways to activate cells.

”That is one of the pretty parts here,“ he said. ”So much is going into turning this [itch signal] down and not so much turning it off. Sarah’s research starts to tell us that.“

Only in recent years have funding agencies, such as the National Institutes of Health, and teams of researchers begun focusing aggressively on solving the mysteries of itching.

"We’ve reached that proverbial point where everyone is interested and the reason why is that there’s some knowledge and hope and drive to find these things. It’s a mix that just wasn’t there before,” Dr. Lerner said, noting the importance of understanding why we itch and how to stop it. "Itching can be worse than pain. When you itch, it’s hard to concentrate and you really have to scratch. You can’t ignore it.”

David Templeton: or 412-263-1578.

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