Genes that fly in the face of pain

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  Genes that fly in the face of pain

by Parizad Bilimoria

Children’s neurobiologists Michael Costigan, Shane Cronin, and Clifford Woolf (left to right) are part of an international team that recently identified a new human pain gene. This gene encodes α2δ3, a component of calcium channels, and controls pain sensitivity in flies and mice in addition to humans.
Credit: Patrick Bibbins

Ever wonder why some people are less sensitive to pain than others? It’s not simply that they’re brave, and the rest of us are wimps. Classic studies of twins indicate that about 50 percent of variance in pain sensitivity is inherited.

“Across a number of different kinds of pain, genes seem to be at least half the driver of how much pain you experience,” says Clifford Woolf, MB, BCh, PhD, director of the F.M. Kirby Center and Program in Neurobiology at Children’s.

Four years ago, Woolf’s lab found the first of these genes, encoding an enzyme that controls pain sensitivity and persistence in humans. Another gene, identified around the same time by a group in the United Kingdom, encodes an ion channel (a pore through which electrically charged atoms enter and exit cells) that also controls pain sensitivity. That gene was found by studying a “firewalker” in Pakistan who was able to walk on burning coals.

The newest human pain gene, discovered by Woolf’s lab in collaboration with the Institute of Molecular Biotechnology in Vienna and the University of Erlangen in Germany, comes to us thanks to fruit flies.

Hot flies and mice

Credit: Patrick Bibbins

While insects might not experience the sensation of pain the way people do, they must—like all living organisms—detect and avoid danger. Normal flies, when introduced to a painfully hot chamber, will fly right out. The beauty of using fruit flies to study pain is that their genes can be mutated easily, and droves of them can be studied at the same time.

So, in a study that just came out in Cell, the investigators targeted nearly 12,000 different genes in flies for mutation specifically in nerve cells, using RNAi technology.

Then they looked for those odd flies that didn’t fly out of the hot chamber, and that didn’t have other complicating factors, such as an inability to see or move well—reasoning that these flies were not detecting the noxious heat. This yielded hundreds of candidate pain genes, but the researchers zeroed in on one: it encodes α2δ3, a component of calcium channels (ion channels through which calcium ions pass). Calcium channels are critical for the electrical excitability of nerve cells, and another unit of calcium channels, closely related, is a known target of some existing pain medications—namely, pregabalin (Lyrica) and gabapentin (Neurontin).

The researchers next moved on to mice. Not only did mice lacking α2δ3 fail to scurry away from painful heat, but functional MRI imaging of their brains give some clue to how the gene works. Unlike other pain genes studied so far, it controls pain processing within the brain itself, not in the nerves carrying pain signals to the brain. The heat pain signal seems to arrive appropriately at the thalamus, an early processing center, but doesn’t travel to higher order pain centers in the cortex.

What’s intriguing is that the mice instead show a cross-activation of vision, olfaction and hearing areas in the cortex. Such cross-activation is thought to underlie synesthesia—experiences like “seeing” music or “smelling” pictures, associated in humans with creativity.

The human connection

But does α2δ3 control pain in humans? To find out, Michael Costigan, PhD, of the Children’s Neurobiology Program, with colleagues at the University of Pittsburgh and the University of North Carolina, examined volunteers’ DNA and found tiny variations within or close to the α2δ3 gene.

Some of these variations, or single nucleotide polymorphisms (SNPs), were associated with decreased sensitivity to acute pain — in a test involving a quick series of noxious heat pulses. People with these SNPs were also less likely to suffer chronic pain after undergoing back surgery for herniated vertebral discs. Disc surgery can have very different outcomes, ranging all the way from curing to worsening the pain – and α2δ3 variations may be one reason why.

Children’s neurobiologists Clifford Woolf and Lee Barrett (left to right), along with Michael Costigan (not shown) and others discovered that KCNS1—a gene encoding a component of potassium ion channels—controls pain sensitivity in humans. They’ve also recently collaborated on new research identifying an ion channel important for cold hypersensitivity.
Credit: Patrick Bibbins

The international team plans to investigate the other pain genes identified in the fly screen. Recently, starting in a rat model, Costigan and Woolf identified a gene encoding a component of potassium ion channels, KCNS1, as a human pain gene. Variations in KCNS1 accounted for significant differences in the level of chronic pain suffered by patients who had undergone disc surgery or limb amputation, or had sciatica—as well as differences in acute pain sensitivity in healthy volunteers. The two have also participated in new research identifying an ion channel key to cold hypersensitivity.

In addition to suggesting new molecular targets for analgesics, the discovery of pain genes could improve doctors’ ability to weigh the risks and benefits of surgery for different patients.

“The way I like to think of it, we have a ‘pain fingerprint’—our own unique pain phenotypic and genotypic characteristic,” Woolf says. “We are trying now to use a panel of the pain genes we’ve found— α2δ3, KCNS1 and others—to develop a genetic risk profile and then say, if you combine these polymorphisms you have a 60 percent chance of chronic pain after surgery, versus say, if you have another polymorphism mix, a 5 percent chance. This is another way to personalize medicine.”

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