Pain. Exciting Renaissance for Sodium Channels, 9 of them


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Exciting Pain Discoveries at UCSF with

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Tarantula Toxins

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UCSF group of 20, including Allen Basbaum,

published yesterday in Nature:

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Selective spider toxins reveal a role for

the Nav1.1 channel in mechanical pain

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I’ve condensed the article by Chelsea Leu in Wired

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UCSF’s David “Julius is a physiologist studying pain, and the toxins in … venoms make you hurt in different ways. By looking at how and where those toxins attack different parts of the nervous system, Julius and his lab might find some that could be used to develop better painkillers.”

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There are many ways to feel pain:

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Thermal – when you burn yourself w ice, eat a hot pepper

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Chemical – “when lactic acid builds in your legs during a run or your cells get damaged.”
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Mechanical – “pain of having a giant, bristling tarantula sink it’s fangs into your hand”

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“And then there’s the big slug of venom that spider delivers straight to your nervous system, a searingly painful combination of any of the three prior types.”

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…”Basically, they are finding new ways to inflict pain,” says Chris Ahearn a biophysicist at the University of Iowa.”

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“Now, Julius and his coauthors have published the latest results of their search in today’s Nature. They isolated two kinds of toxins from the venom of a tarantula called Heteroscodra maculata, and discovered it causes mechanical pain. That’s what you feel when your body gets pinched or strained or prodded, and it also underlies chronic pain in afflictions like irritable bowel syndrome. When the scientists injected mice’s paws with small doses of the toxin, they became much more sensitive to getting poked.”

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…sodium channels…..

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…”tarantula venom, though, has two toxins that target a very specific type of sodium channel. And once scientists figured that out, they deduced that those sodium channels control mechanical pain.”

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That link could be key to developing new painkillers. Scientists had sort of overlooked sodium channels before, says Ahern, ignoring the nuances between the types—each is big and complex, and the nine types of channel aren’t all that structurally different. But those nuances turn out to be very important.

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“It’s kind of a Renaissance for sodium channels,” *********Ahern says. And drug companies would love to target specific sodium channels to get at some types of pain and not others.

Case in point: The local anesthetics doctors use now, like lidocaine, block all sodium channels. That shuts down all nerve communication in an area for a short period of time. Which is fine if you’re getting a root canal, but not so great for recurring ailments like back pain. “The pharmacology of pain is still pretty primitive,” Julius says. And the medicines that treat chronic pain—opiates, mostly—aren’t too swell either. “Opiates are embarrassingly blunt,” says Jeremiah Osteen, a post-doc in Julius’ lab who led the Nature study. “They don’t do anything to the pain signal itself, they just dampen the body’s response to it.

 

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[Interrupting this to say: Exactly.

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“opioids do nothing to the pain signal itself” as opposed to glial modulators that help to restore balance within the innate immune system.

Pardon our ignorance. Now begs questions:

1. Please remind us what triggers each type sodium channel.

2. Glial modulators help to”reset” the sodium channels. Is that correct?

3. Do sodium channels and glia interact? How?

 Any hints would be lovingly appreciated.]

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Cont’d

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“So, more knowledge of what controls different types of pain could mean better pain meds. And those channels might be helpful in targeting other, non-pain conditions. For instance, the sodium channels targeted by the Heteroscodra maculata‘s toxins hadn’t really been studied before in the context of pain, but scientists had previously discovered that mutations on that channel often cause epilepsy. Julius and his team suggest the toxins they found could be fruitful starting points for epilepsy researchers to develop drugs. [of dual use drugs epilepsy and pain.]

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In pursuit of pain

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Julius’s lab didn’t pull those tarantula toxins out of a hat. With hundreds of venoms in their library to sort through, they’ve developed a systematic, laborious process to home in on the interesting ones. “We’re screening pretty much continuously,” Osteen says. They test every new venom they get by applying each to mice and rat nerve cells in a dish. If a subset of the cells lights up—showing up neon blue against a purple background, thanks to a calcium dye—it’s a sign that the venom is targeting some pain receptors and not others.

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Of the venoms they test, about 15% turn up promising. From there, it’s a matter of winnowing out the toxins they find interesting. The trickiest parts, Osteen says, are figuring out what exactly each toxin is and where exactly it’s targeting. The lab separates out the promising venoms into their individual toxins, in almost imperceptibly tiny droplets. (“They’re very potent,” Osteen says.) To determine what’s what, they use mass spectrometry, sequence proteins, analyze genes in the animals’ venom sacs, and synthesize the toxins. Sometimes, they call in specimens of the venomous animals themselves to collect RNA (molecules that show which genes are being expressed and when). Then, the scientists throw out the toxins that have been studied extensively, and delve into the rest.

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The lab isn’t stopping at a couple of toxins that may be medically promising, however. Julius and his colleagues are intent on figuring out how the entirety of pain works, doing what Osteen calls “curiosity-based science.” Of course, they’ll look closely at any serendipitous medical discoveries that might branch from their research, but they’re mostly researching this stuff because, well, it’s cool. Why wouldn’tyou want to learn all about venom?

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Still, their work is eminently practical. Pain is universal, Julius points out, and it’s something everyone is viscerally interested in. “On a fundamental level,” he says, “it shapes how we experience the world.” Though the experience of a debilitating tarantula bite might be one you’d want to stay a world away from.

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