Imagine having personalized medical care—treatments matched not only to a person’s specific illness but also to that person as an individual patient. In this scenario, doctors would use medications only in instances where they were known to work, potentially causing fewer side effects. That level of care might sound like a pipe dream—and for the most part, it still is.
But scientists are working to bring personalized medicine (also often referred to as precision medicine) within reach of people with chronic pain. Leading the charge is a group of researchers studying individuals with pain that is linked to genetic mutations in a specific family of proteins called sodium channels.
At the 2017 annual meeting of the Society for Neuroscience (SfN), the group, led by Sulayman Dib-Hajj and Stephen Waxman at Yale University School of Medicine, New Haven, and Veterans Affairs Medical Center, West Haven, US, presented several research posters describing their latest work. These provide an exciting look, from the cutting edge of knowledge, into what the future could be like in a world of personalized treatments for pain.
The SfN meeting is the world’s largest neuroscience conference for scientists and physicians seeking to understand the brain and nervous system. The event took place in November 2017 in Washington D.C. (See additional coverage of the meeting here).
Sodium channels spark the firing of nerve cells
Nerve cells (neurons) are electrically excitable, which makes them capable of extremely fast communication. This electrical excitability is driven by tiny proteins in a neuron’s membrane, called ion channels, through which charged particles flow.
Those particles, known as ions, include sodium, chloride, potassium and calcium ions, and they can shift a cell’s electrical charge (changes in the electrical excitability of neurons are measured in millivolts). Some sodium ion channels open in response to tiny voltage changes and are crucial in triggering a neuron to fire electrical signals called action potentials.
One type of sodium channel, called Nav1.7, is of great interest to pain researchers and pharmaceutical companies in search of new pain medications (see a related RELIEF feature article published last year). Interfering with Nav1.7 channels showed early promise as a way to modify electrical signals coming from pain neurons in the peripheral nervous system (outside the brain and spinal cord), which is where these channels reside. This is in contrast to other types of Nav channels present in the heart and brain, which are required for basic survival. If researchers could find a way to manipulate Nav channels present only in pain neurons, while leaving the others undisturbed, it might be a way to safely dampen pain.
A major step in understanding Nav channels came with the discovery of a mutation in the gene that encodes Nav1.7 channels, called SCN9A, in people with a rare condition that leaves them unable to feel pain. While this so-called congenital insensitivity to pain (CIP) might sound attractive, it is actually a life-threatening disease, because pain serves as a vital warning signal to avoid potentially harmful threats in the environment. The mutation makes the channels mostly inactive, which quiets the electrical signals that pain neurons send into the spinal cord.
Other mutations in SCN9A can have the opposite effect on the channels, that is, they make them more active than usual. These overactive channels cause some cases of inherited erythromelalgia (IEM), which causes burning pain, usually in the hands or feet, in response to warmth or mild exercise, and another condition called paroxysmal extreme pain disorder (PEPD). (Many people have EM or PEPD with no known cause.)
Waxman and Dib-Hajj’s team has been instrumental in research linking genetic mutations in SCN9A to rare pain conditions, as well as to more common conditions like small fiber peripheral neuropathy (SFPN). More recently, they have been working to understand the consequences of individual mutations in hopes of finding personalized treatments.
A mutation with mixed results
It is not surprising that overactive sodium channels would cause pain conditions, and that inactive Nav1.7 channels would preclude the ability to sense pain. But some patients present with a confusing mix of symptoms not so easily explained.
One such case was the basis for research presented by Jianying Huang, a junior research faculty member. A young girl suffered from symptoms of both IEM and PEPD, with red, burning hands and random “lightening” strikes of pain to the extremities. But she also had unusual symptoms suggesting impaired pain sensation. When she was ten, for instance, the girl developed a fracture to her thigh bone that went undetected for an entire day before an X-ray revealed it. Another patient, identified by a different group of investigators, had similar pain symptoms, and an inability to feel pain upon scratching the cornea of his eyes. The researchers detected the same mutation in the SCN9A gene in both individuals. Could it explain both types of symptoms—the pain, and the lack of pain?
To answer this question, it’s important to understand how pain neurons become excited. In a quiet state, a neuron’s membrane sits at a “resting potential,” or voltage. When something potentially dangerous in the environment (such as very high temperatures or chemicals) activates nerve endings, the membrane becomes slightly “depolarized,” or excited. Even slight excitation can cause Nav1.7 to open, further boosting the excitatory signal. If the nerve becomes excited enough to fire action potentials, it will send the signal into the spinal cord.
Dib-Hajj and his colleagues tested how Nav1.7 channels with the young girl’s mutation, called I234T, behaved compared to normal Nav1.7 channels in sensory neurons isolated from rats. Mutations that cause IEM and PEPD are called gain-of-function, because they make the channel more active. Specifically, they make Nav1.7 channels open in response to smaller excitations than usual, so that even the tiniest electrical signal can reach the spinal cord. Usually, these mutations shift the activation voltage (the voltage at which the channel opens) of Nav1.7 by about five to 12 millivolts (mV), making them hyper-excitable. In contrast, the I234T mutation found in the girl shifted the channel’s activation voltage by 18 mV, making it even more hyper-excitable than other mutant channels.
“The data are unambiguous,” says Dib-Hajj. “It’s a gain-of-function mutation that leads to more depolarization,” or excitation, which is consistent with the severe pain experienced by this patient. The challenge, however, was to explain the painless bone fracture.
To address this issue, the researchers also classified rat peripheral sensory neurons containing either the normal or mutant Nav1.7 channels by how easily they fired action potentials. A majority of neurons containing channels with the I234T mutation were more excitable, and the threshold at which the cells fired was much lower than normal. But a small fraction of the cells—about ten percent—did not fire action potentials no matter how much the researchers stimulated these neurons. On the other hand, a slim majority of neurons containing the normal (also known as the “wild-type”) channel fell into the less-excitable bin, but all neurons fired action potentials in response to electrical stimulation.
“The mutation caused a massive shift in resting potential,” Dib-Hajj said—that is, enough electrical excitement to activate the mutant channels even in the absence of potentially harmful stimuli that can lead to pain. But in some cells, once the channels open, they become inactivated and can’t open again for a while. In that small segment of cells that did not fire, “the mutant channels are spending more time in the inactivated state, effectively freezing the neurons in an unresponsive state,” he said.
So, neurons with the I234T mutation by and large became more sensitive and more active, but a sliver of them becomes silent—perhaps explaining the girl’s unusual mix of painful and painless symptoms. (The study was since published in the journal Scientific Reports).
Treating hyperactive channels
Effective treatments for pain from nerve injury, known as neuropathic pain, are extremely limited, and conditions caused by SCN9A mutations, which are found in some patients with neuropathic pain, are no exception. But the researchers noticed that a small number of inherited erythromelalgia (IEM) patients—these are the ones with burning pain—did respond to a drug used for epilepsy, called carbamazepine, which quiets sodium channels but rarely helps patients with IEM or nerve damage.
Previously published research from the group had found that the patients who responded to the drug all had one particular mutation. To find out what made it special, the researchers used computer modeling of the channels’ shape. This, and additional analysis, allowed them to accurately predict that patients with a different mutation would also respond to the drug. The two mutations that made the channel sensitive to carbamazepine both affected the same region of the channel. (See a related IASP Pain Research Forum news story here.)
A young research assistant in the group, Talia Adi, presented research at SfN she carried out together with Yang Yang, who recently became a professor at Purdue University, West Lafayette, US. They found that the I234T mutation was also sensitive to carbamazepine. “We used a structural modeling approach to see if this third mutation affected the same zone of the channel” as the two earlier identified mutations, Adi said, which it did.
The researchers then recorded electrical activity from rat sensory neurons containing the I234T mutant channels. These cells were spontaneously active, as expected. “But when we put carbamazepine on the cells, it significantly reduced their excitability,” Adi said. (The study was published in 2017 in the British Journal of Pharmacology).
Yang and Adi found that the drug worked differently at the I234T mutant channels than it normally does at sodium channels. Instead of simply stemming the flow of ions through the channels, carbamazepine seems to alleviate the hypersensitive activation of the channels, by shifting the voltage at which the channel opens. “The drug definitely shifts the channels’ activation by six millivolts—correcting about a third of the shift caused by the mutant, but not all the way,” she said.
The bottom line for doctors, Dib-Hajj tells RELIEF, is that “any patient that shows up with this mutation should try carbamazepine, after ensuring there are no known contraindications for that drug.”
Mark Estacion, an author on the research posters presented at the meeting, told RELIEF, “I’m proud to be part of this effort to achieve precision medicine. Even if we only help a few patients at a time, that gives us the incentive to keep going. It is hugely motivational to actually be helping patients.”
While the findings may be limited to a very small number of patients right now, the insights into how Nav1.7 channels work could benefit the search for drugs that will help much larger patient populations.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.