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Got Pruritus? New Neural Pathway Identified to Target the Common Itch

Talan, Jamie

doi: 10.1097/01.NT.0000432682.93546.0d
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Investigators have uncovered what they say is the molecular trigger for itch — a neuropeptide called natriuretic polypeptide b. When the molecule was knocked out in mice, the itching sensation stopped.

A relatively new field in neuroscience — mapping out the acutely annoying and sometimes unbearable itch, or pruritus — has found itself scratching at a cellular puzzle: a surprising molecule in the neuronal pathway for the sensation of itch. When the molecule or its nerve cell was removed, the itching sensation stopped — at least in mice. The discovery suggests a potential new therapeutic target.

Mark A. Hoon, PhD, and Santosh K. Mishra, PhD, scientists in the molecular genetics unit in the laboratory of sensory biology at the National Institute of Dental and Craniofacial Research, were looking for signaling components of somatosensory neurons that contain a molecule called transient receptor potential cation channel subfamily V member 1 (TRPV1); these neurons are activated by heat, touch, and other painful conditions. They learned that a neuropeptide — natriuretic polypeptide b (Nppb) — was expressed only in a subset of these TRPV1 neurons.

Transgenic mice that did not express Nppb lost virtually any behavioral (scratching) response to itch-inducing agents. And when the neuropeptide was injected into the spinal cord in these Nppb knockout mice they started aggressively scratching. Itch responses were also blocked when they used a toxin to destroy Nppb-receptor-expressing cells in the spinal cord. The results led the investigators to conclude that Nppb is the primary neuropeptide that governs itch. The findings were reported in the May 29 edition of Science.

“These cells, at least in the spinal cord, are specialized to control itch,” said Dr. Hoon. Nppb was first seen in the heart, where scientists found that it controls blood sodium and blood pressure. Its role in the heart makes developing a treatment selectively targeted for Nppb-enriched neurons challenging, he added.

Nppb isn't the first substance that has been linked to pruritus, and the finding may ultimately lead to some debate about the pathways involved in itch. In 2007, scientists identified gastrin-releasing peptide (GRP) as a mediator of itch and many labs have now been working on developing treatments that block the uncomfortable sensation, which can lead to mild to unrelenting scratching.



In their latest study, published in Science, Dr. Hoon and Dr. Mishra found that GRP continued to induce a strong response in the animals with ablated Nppb-receptor-expressing cells, demonstrating that GRP is working further downstream of Nppb in the itch circuitry.

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About five years ago, two independent groups identified TRPV1's involvement in itch. No one knew much about TRPV1's exact role in the itch pathway. Dr. Hoon and his colleagues generated a group of transgenic animals without TRPV1-expressing neurons. The knockout animals had changes in many neuronal cell types. The animals showed no response to hot and cold temperature, or to chemicals that would normally cause them to scratch. The animals appeared to have normal mechanical pain sensations — they would respond to the poke of a needle — but a toxin known to produce pain did not seem to bother them. These puzzling changes led the researchers to wonder whether they could further differentiate TRPV1's role in pain, responses to thermal regulation, and itch.



They used a microarray screen that identified many TRPV1-enriched transcripts and identified Nppb. They reported that Nppb is “prominently expressed in a small subset of dorsal root ganglia neurons and dramatically decreased in sensory ganglia.” All of the Nppb-expressing neurons contain TRPV1 and an effector enzyme called PLCbeta3 that had also been linked to histamine-induced scratching in mice.

They generated a line of animals that do not express Nppb and found that the animals appeared healthy and “had normal numbers of nociceptive, touch and proprioceptive neurons.” The number of dorsal horn interneurons was also normal. Standard assays showed that the animals had no problems in response to thermosensory and pain stimuli. But things got markedly abnormal in their response to compounds that send a normal animal into intense bouts of scratching. Nothing seemed to provoke itching, which lead Dr. Hoon and his colleagues to the idea that itch has its own place in the sensory world and is distinct from the experience of pain and temperature.

He said that the challenge ahead is to identify similar cellular circuitry in humans and then figure out how to target specific molecules to stop itch sensations in patients with chronic problems. “This is not a trivial thing to do,” said Dr. Hoon.

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Zhou-Feng Chen, PhD, professor of anesthesiology, psychiatry and developmental biology and director of the Center for the Study of Itch at Washington University School of Medicine, was trying to identify receptors for pain transmission when he happened onto gastrin-releasing peptide receptor. It didn't appear that GPR receptor had a role in pain processing but he found that animals that lacked the gene for the receptor are resistant to compounds that trigger itch. Not unlike Dr. Hoon's study, stimulation with GRP tripped an intense scratching session.

He does not believe, as Dr. Hoon suggested in the paper, that the GRP is downstream in the itch circuitry. “It's too early to say where these molecules are in the itch pathway,” said Dr. Chen, who opened the Center for the Study of Itch in 2010.

Dr. Chen said that other researchers have pointed out Nppb's role in inflammatory pain. He added that the federal team did not study chronic itch. He said that they did similar studies to knock out GRP receptor (published in Science in 2009) and found that the mice did not scratch in response to itch-provoking substances, and their pain responses were normal. His team recently collaborated with scientists at Wake Forest University to find that GRP peptide and receptors are increased in monkeys with chronic itching conditions.

Robert LaMotte, PhD, professor of anesthesiology and neurobiology at Yale University, agreed that a lot of clever work went into these experiments but “you can't always tell by the absence of a response. They need to continue working on this idea,” he said.

The scientists have proven that the itch sensation is separate from pain pathways. But the details are still not mapped out. “It was quite a surprise,” said Earl E. Carstens, PhD, a professor in the department of neurobiology, physiology & behavior at the University of California, Davis. “The NIH study makes a lot of sense. Nppb is released from primary sensory neurons. GRP is produced by the spinal cord so it may be a second transmitter downstream.”

He suspects that there are multiple neurotransmitters called upon that spark an itch. “The answers are not there yet. This puts another peptide into the mix.”

Dr. Carstens said that the itch sensation provides a warning signal to the organism that a potentially harmful parasite or plant material is invading the skin. Itch sensation is closely linked with scratching behavior, so the itch triggers scratching directed at the itchy site in the skin to remove the plant material or parasite from the skin surface or to dig it out if it has entered into the skin.

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•. S Mishra, M Hoon. The cells and circuitry for itch responses in mice. Science 2013; 340 (6135): 968–971.
    •. Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007; 448(7154):700–703.
      •. Sun YG, Zhao ZQ, Meng XL, et al. Cellular basis of itch sensation. Science 2009; 325(5947):1531–1534.
        •. Mishra SK, Tisel SM, Orestes P, et al. TRPV1-lineage neurons are required for thermal sensation. EMBO J 2011;30(3): 582–593.
          •. Neurology Today's article: New research shows itch is a lot more than skin deep:
            © 2013 American Academy of Neurology