Wednesday, June 12, 2013

Scientists identify two classes of itch neuron by turning them off separately

For several years it’s been known that itch and pain signals from the skin are carried by different types of neuron to the spinal cord and brain. But there's more than one kind of itch. Scientists have now clearly identified at least two types of itch neuron—one that responds to histamine and a second type that responds to other itch-provoking molecules.

These results could lead to drugs that selectively shut down chronic itch in eczema patients but leave the rest of the sensory system intact.

Some itch is caused by histamine, which triggers an itch signal in certain neurons. But histamine is not the main source of itch for eczema patients. In eczema, most itch has its origins in allergy, when mast cells release “pruritogens” that bind to receptors on itch neurons.

For a long time it was an open question whether histamine and the other pruritogens were triggering itch signals in the same neurons, or different types that scientists could distinguish experimentally.

In late May, researchers led by Alexander Binshtok at the Hebrew University in Jerusalem and Clifford Woolf at Harvard Medical School reported results that clearly showed histamine and non-histamine itch signals are carried by different neurons. The research was published in the journal Nature Neuroscience.

The scientists used a novel two-stage experimental technique to shut the two neuron types down independently. Perhaps someday a similar technique might be embodied in an anti-itch therapy.

What they did was to exploit the fact that when neurons detect histamine and pruritogens, large-diameter channels open in the neurons to let in ions (charged particles) that initiate the electrochemical itch signal, which relies on sodium and potassium.

First, the scientists treated mice with either histamine or a non-histamine pruritogen. At the same time they injected the mice with QX-314, a molecule that blocks sodium ion channels (which are very small-diameter). The large-bore ion channels opened to let in sodium, potassium, and QX-314.

Thereafter, those neurons were unable to fire itch signals, because their sodium channels were blocked by QX-314. The scientists showed that when they dosed the mice with histamine and QX-314, one group of neurons didn’t work (and the mice didn't scratch). When they dosed the mice with other pruritogens and QX-314, the histamine itch neurons worked, but other subsets of neurons were shut off (and the mice didn't scratch).

The scientists’ technique is not directly translatable to therapy, because this study was conducted in mice and involved injection, which is not practical for daily use. But the molecular action they were studying takes place in the upper skin layers, and one could imagine that someday a cream or ointment might be developed that would include two components: one to open large-bore ion channels that detect pruritogens, and another to block the electrochemical signals in those neurons.

Hat tip to Ryan.

PS in a recent post I discussed the difference between TRPV1 ion channels, required for histamine itch, and TRPA1 channels, required for chronic itch. These are the "large-bore" channels mentioned above. Trivia: To trigger a histamine itch signal in a neuron, histamine must activate both TRPV1 and the H1 histamine receptor. To trigger a non-histamine itch signal in a neuron, a pruritogen must activate both TRPA1 and a special pruritogen receptor--"MrgprC11" in the case of dry skin.

6 comments:

  1. Huge credits to to the scientist's discovery of the "anti-histamine" of eczema-induced itch.
    And thank you for further break down of the new research for easier understanding!

    Probably any new cream or ointment invented based on this new research will not have any permanent anti-itch effect as I highly doubt that QX-314 molecules would stay around in the TRPA1 channels for that long. Nevertheless, I hope that it would at least last longer than some of the current treatments.

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    1. Hi Ryan,

      Thanks for your interest in our research! You are right that the effect of QX-314 treatment would not be permanent. However our previous experiments with QX-314 show that the sensory block lasts for about 24 hours in mice. This is a bit surprising since regular lidocaine only blocks sensation in mice for 15-30 minutes. We think that QX-314 (charged lidocaine) lasts so much longer because the molecule gets trapped in the nerve due to its positive charge. Regular lidocaine, on the other hand, does not have a permanent charge so it can freely pass out of the neurons through the cell membrane.

      Best,

      David Roberson
      Harvard Medical School

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  2. Thank YOU for telling me about this research.

    I'm not sure how long QX-314 has an effect. But drug discovery folks specialize in tweaking molecules to make them stick more or less tightly to binding sites. So most likely a better molecule is out there.

    What is funny is that the technique used by the scientists in this case would actually make you MORE itchy for about ten or fifteen minutes, before shutting off the itch completely. I don't know whether patients would go for that!

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    1. Hi Spanish Key,

      I'm very impressed with your summary of our recent research article about itch in Nature Neuroscience. The article is admittedly a tough read, but you have done a great job hitting all the key points concisely and in plain English. Great work!

      We didn't mention this in the article because it is still a bit speculative, but we think that a treatment using QX-314 (or some related compound) may not require co-administration with an itch-causing agent since chronic itch conditions likely involve ongoing activation TRP channels. It was necessary to co-administer histamine or chloroquine with QX-314 in our study because the mice did not have a chronic itch condition to start with.

      We are now doing mouse experiments looking at topical application of QX-314 for clinically relevant chronic itch conditions. Our preliminary results look promising. We plan to present these findings at the upcoming 7th World Congress on Itch in September in Boston.

      Keep up the great work on you Blog. This is a great resource to keep up with the latest work in the itch field!

      Best,

      David Roberson
      Harvard Medical School

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    2. Excellent, thanks David--there's nothing better for this blog than comments by actual researchers. I'll check out the conference proceedings.

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  3. Thanks for posting about the research. Very interesting that they discovered the "anti-histamine" of eczema-induced itch. Thanks for sharing! Keep up the good work

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