Recently scientists reported the discovery of an “itch molecule” (Nppb) responsible for conveying the itch signal across the synapse from sensory neurons in the skin to neurons in the dorsal horn of the spinal cord.
The media made a great deal of this study, which laid out a substantial model for how we feel itch.
Something I hadn’t noticed, though, was that the Science study considered only a subset of neurons involved in sensing itch—those that are activated by histamine. These neurons, at the itch-sensing end, have a type of ion channel called “TRPV1” that detects histamine and other substances, or “pruritogens,” that induce itch.
An ion channel is a kind of gate that opens when a key--such as a histamine molecule--binds to it. The open gate lets in sodium or potassium ions. When this happens to ion channels in a neuron, the neuron sends an electrical pulse down its length, transmitting information, such as a sensation of itch.
But there are other triggers for itch besides histamine. “Histamine-independent” itch is particularly important in the chronic itch experienced by eczema patients. (And that's why antihistamines don't do us any good.)
Histamine-independent itch is transmitted by neurons that possess TRPA1 ion channels. A new study, published in the Journal of Neuroscience, shows that mice only feel chronic itch if they have neurons expressing TRPA1 channels. Strikingly, the scientists show that knocking out TRPV1 channels (the histamine-dependent kind) does not affect the ability of mice to feel chronic itch.
As a model of chronic itch, the researchers shaved the cheeks of lab mice and exposed the skin to drying chemicals over a period of a few days. The mice scratched their cheeks and developed classic signs of dry, itchy skin--unless their TRPA1 channels had either been genetically deleted or inhibited by a drug,in which cases they hardly scratched at all.
The researchers were also interested in whether the itch-scratch cycle affected the sensation of itch. If you don’t scratch an itch, does it get better or worse? The answer appears to be that if you (or, by proxy, a lab mouse) have an itch on your back that you can only scratch by rubbing it against the wall, it may torment you, but when measured by objective standards, skin that you don’t scratch ends up in better shape.
We can draw two practical conclusions from this work, which was led by Diana Bautista at UC Berkeley: that blocking TRPA1 channels with a drug in cream or ointment form could be a potential solution to the chronic itch of eczema; and that it really does appear that if you can break the itch-scratch cycle, your skin will be better off.
Now, we all know how difficult it is to stop scratching. It’s not as easy as saying that you’ll stop. But this type of research certainly highlights the positive feedback of habit-reversal, which uses psychiatric techniques to reduce habitual scratching. Scratch less…and you’ll feel less itchy.
I do have one question: does the molecule Nppb, reported in the
Science paper two weeks ago, transmit chronic itch signals as well as
histamine-induced itch? If so, it is still a valuable target for further
research into eczema therapies.
Showing posts with label neurons. Show all posts
Showing posts with label neurons. Show all posts
Tuesday, June 4, 2013
Tuesday, May 28, 2013
"Itch molecule" discovery a big step forward
All over the media last week was the news that two scientists at the National Institutes of Health in Bethesda, MD had discovered “the molecule responsible for itch.”
This molecule, “Nppb,” relays signals from certain neurons that detect itch in the skin to other neurons that carry the signals up the spinal cord to the brain. The scientists, Santosh Mishra and Mark Hoon, engineered mice in which the gene for Nppb had been turned off. The mice could not, apparently, feel itch.
The media hype is evident. Nppb is not THE molecule responsible for itch. Several molecules are known to be involved in detecting itch in the first place, and we know many others must be involved in the signaling pathway.
What is remarkable, though, is that the scientists were able to define a model for how itch gets from the skin to the spinal cord.
We now know that there are at least two pinch points: the synapse across which Nppb carries the signal, and a second downstream synapse across which another molecule, GRP, sends the information to the next stage of neurons.
Blocking the receptors for Nppb or GRP would seem to be a prime candidate for an anti-itch therapy.
But, of course, there are complications. Nppb was originally known because it is important in the heart, where it controls blood pressure. GRP controls digestion. The genetically engineered Nppb-free mice died early. (The scientists said so in their media interviews.)
So you can’t just take a pill that blocks Nppb receptors everywhere. That would be a disaster.
But this kind of restriction on where a drug can act is well-known in pharmacology. That’s why, e.g., I can use the anti-pain Voltaren gel (diclofenac) safely by rubbing it into my joints, but diclofenac is known to be pretty toxic if you swallow it.
You can’t design an Nppb receptor-blocking topical cream, because the important synapses are in the spinal cord. A cream would only be effective on the surface.
But it might be possible to take a pill that blocks Nppb only in the spinal cord. I’m not sure how, but that’s what major pharma companies are paying their scientists the big bucks to find out. Maybe the receptors in the spinal cord are subtly different than those elsewhere in the body.
This is very exciting stuff. The massive question is whether the work applies to humans. I would expect it did. Mice and human immune systems are quite different, but our nervous systems are not. We most likely have an analog of Nppb that carries our itch signals.
Just to put this in context—the new work tells us substantially more about itch signaling than previous work in the field. I’d been aware of studies that had identified a class of itch neurons, or certain molecules important in detecting itch in the skin, but this research builds on those foundations in a big way.
This molecule, “Nppb,” relays signals from certain neurons that detect itch in the skin to other neurons that carry the signals up the spinal cord to the brain. The scientists, Santosh Mishra and Mark Hoon, engineered mice in which the gene for Nppb had been turned off. The mice could not, apparently, feel itch.
The media hype is evident. Nppb is not THE molecule responsible for itch. Several molecules are known to be involved in detecting itch in the first place, and we know many others must be involved in the signaling pathway.
What is remarkable, though, is that the scientists were able to define a model for how itch gets from the skin to the spinal cord.
 |
| Mishra and Hoon's model of how neurons carry the itch signal. (Fig 4G from their Science paper.) |
We now know that there are at least two pinch points: the synapse across which Nppb carries the signal, and a second downstream synapse across which another molecule, GRP, sends the information to the next stage of neurons.
Blocking the receptors for Nppb or GRP would seem to be a prime candidate for an anti-itch therapy.
But, of course, there are complications. Nppb was originally known because it is important in the heart, where it controls blood pressure. GRP controls digestion. The genetically engineered Nppb-free mice died early. (The scientists said so in their media interviews.)
So you can’t just take a pill that blocks Nppb receptors everywhere. That would be a disaster.
But this kind of restriction on where a drug can act is well-known in pharmacology. That’s why, e.g., I can use the anti-pain Voltaren gel (diclofenac) safely by rubbing it into my joints, but diclofenac is known to be pretty toxic if you swallow it.
You can’t design an Nppb receptor-blocking topical cream, because the important synapses are in the spinal cord. A cream would only be effective on the surface.
But it might be possible to take a pill that blocks Nppb only in the spinal cord. I’m not sure how, but that’s what major pharma companies are paying their scientists the big bucks to find out. Maybe the receptors in the spinal cord are subtly different than those elsewhere in the body.
This is very exciting stuff. The massive question is whether the work applies to humans. I would expect it did. Mice and human immune systems are quite different, but our nervous systems are not. We most likely have an analog of Nppb that carries our itch signals.
Just to put this in context—the new work tells us substantially more about itch signaling than previous work in the field. I’d been aware of studies that had identified a class of itch neurons, or certain molecules important in detecting itch in the skin, but this research builds on those foundations in a big way.
Tuesday, May 21, 2013
Where to look for a surprise eczema cure to emerge
As I wrote in the previous post, the outlook is bleak for new eczema therapies that might qualify as a “cure.” On the fronts of barrier protection and repair and anti-inflammatories, nothing revolutionary is in the works apart from, perhaps, dupilumab, Regeneron’s antibody to IL-4. I can’t see anything emerging from research and entering and successfully exiting clinical trials for at least 25 years.
What might I have left out of this discussion? Where could a surprise come from?
Itch. Itch was the area that occurred to me. Imagine being able to break the itch-scratch cycle in eczema. You know what it’s like: your skin flares up and the itch becomes unbearable. You scratch to get relief. Sometimes you scratch in your sleep. Then your skin is torn up, which for a start can be embarrassing, but also often leads to infection. If there were no itch to begin with, eczema might never become anything more than a minor rash. Its impact on quality of life would be greatly minimized.
I believe we might see a convergence of two major trends that would result in a new anti-itch drug that patients could take in pill or cream form.
The first trend: In the past few years I have seen a number of papers describing newly identified neurons that transmit the sensation of itch, distinct from pain. The experiments were done on animals such as mice and cats; I don’t think these neurons have been found in people yet. But you can bet there are many scientists beavering away to be the first in the field.
Turning on or blocking neural receptors is what drugs do best. Think anesthetics. These itch neurons, if found in humans, are likely going to have receptors similar to those in other animals, and the search will be on to find drugs that block the receptors.
(You could also imagine a therapy using RNA interference to prevent neurons in the skin from making itch receptors in the first place.)
The second trend: scientists are developing powerful new techniques to speed the drug discovery process. While it does take around 15 years to take a new drug all the way through clinical trials to FDA approval, the path is shorter for “repurposed” drugs (such as Viagra, originally planned as a heart medication). The barrier is lower because the drug has already been proven nontoxic. Repurposed drugs have been approved as treatments for one condition but have side effects that, depending on your perspective, qualify as primary effects. There could well be an FDA-approved anti-itch drug out there already. It’s just being used to treat toenail fungus.
A company I am familiar with (I know the founders), SeaChange Pharmaceuticals, developed a rigorous way to search through databases of drugs and identify potential side effects or secondary uses, based on the chemistry of the protein targets for the drugs. (Wired magazine named SeaChange’s technology one of the top 10 breakthroughs of 2009.)
The idea would be that scientists would identify itch neurons in humans, and pin down the itch receptor; then somebody at Pfizer or Novartis or whatever would use a SeaChange-like technique to find FDA-approved drugs that block the receptor. Presto: no more itch. Conceivably this might happen within a decade.
Now, evidently these new drug discovery techniques could be applied in the areas of anti-inflammatories, or barrier repair. I think, though, that itch is a prime candidate for a surprise eczema “cure” because it’s likely that the itch sensation comes down to a single receptor. Blocking that receptor by a conventional drug will be a relatively simple task, compared to controlling inflammation without leaving the patient vulnerable to infection, or taking on the dubious task of compensating for a defective skin barrier in infants.
That’s my opinion.
What might I have left out of this discussion? Where could a surprise come from?
Itch. Itch was the area that occurred to me. Imagine being able to break the itch-scratch cycle in eczema. You know what it’s like: your skin flares up and the itch becomes unbearable. You scratch to get relief. Sometimes you scratch in your sleep. Then your skin is torn up, which for a start can be embarrassing, but also often leads to infection. If there were no itch to begin with, eczema might never become anything more than a minor rash. Its impact on quality of life would be greatly minimized.
I believe we might see a convergence of two major trends that would result in a new anti-itch drug that patients could take in pill or cream form.
The first trend: In the past few years I have seen a number of papers describing newly identified neurons that transmit the sensation of itch, distinct from pain. The experiments were done on animals such as mice and cats; I don’t think these neurons have been found in people yet. But you can bet there are many scientists beavering away to be the first in the field.
Turning on or blocking neural receptors is what drugs do best. Think anesthetics. These itch neurons, if found in humans, are likely going to have receptors similar to those in other animals, and the search will be on to find drugs that block the receptors.
(You could also imagine a therapy using RNA interference to prevent neurons in the skin from making itch receptors in the first place.)
The second trend: scientists are developing powerful new techniques to speed the drug discovery process. While it does take around 15 years to take a new drug all the way through clinical trials to FDA approval, the path is shorter for “repurposed” drugs (such as Viagra, originally planned as a heart medication). The barrier is lower because the drug has already been proven nontoxic. Repurposed drugs have been approved as treatments for one condition but have side effects that, depending on your perspective, qualify as primary effects. There could well be an FDA-approved anti-itch drug out there already. It’s just being used to treat toenail fungus.
A company I am familiar with (I know the founders), SeaChange Pharmaceuticals, developed a rigorous way to search through databases of drugs and identify potential side effects or secondary uses, based on the chemistry of the protein targets for the drugs. (Wired magazine named SeaChange’s technology one of the top 10 breakthroughs of 2009.)
The idea would be that scientists would identify itch neurons in humans, and pin down the itch receptor; then somebody at Pfizer or Novartis or whatever would use a SeaChange-like technique to find FDA-approved drugs that block the receptor. Presto: no more itch. Conceivably this might happen within a decade.
Now, evidently these new drug discovery techniques could be applied in the areas of anti-inflammatories, or barrier repair. I think, though, that itch is a prime candidate for a surprise eczema “cure” because it’s likely that the itch sensation comes down to a single receptor. Blocking that receptor by a conventional drug will be a relatively simple task, compared to controlling inflammation without leaving the patient vulnerable to infection, or taking on the dubious task of compensating for a defective skin barrier in infants.
That’s my opinion.
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