Neurons Go Haywire During Pain From Nerve Injury

Neuropathic pain

A new study uses nerve cells from patients with spinal tumors to identify changes in the nervous system underlying neuropathic pain. Image credit: Rostislav Zatonskiy/123RF Stock Photo.

Stinging, burning, electric, pins and needles. Those words are often used to describe chronic neuropathic pain, which is pain that arises from nerve damage. Now, rare recordings of the electrical activity of human nerve cells suggest that spontaneous cell “firing” causes these sensations, according to a new study in patients being treated for spinal tumors.

For the new research, Patrick Dougherty, from the University of Texas MD Anderson Cancer Center in Houston, and Ted Price, of the University of Texas at Dallas, obtained access to human dorsal root ganglion (DRG) neurons in the patients, who were being treated for their tumors at MD Anderson. DRG neurons that detect potential harm relay electrical signals from the body into the spinal cord. When those signals reach the brain, an experience of pain can emerge.

The researchers found that the DRG neurons from the patients showed spontaneous “ectopic activity,” meaning that there were electrical signals emanating from a place, in this case the DRG, in which such signals do not normally originate. The new work thus pinpoints a phenomenon underlying neuropathic pain in people.

In addition, Franziska Denk, a pain scientist at King’s College, London, UK, who was not involved in the new study, said the use of human DRG neurons to study the electrical activity of pain-sensing neurons is a highlight of the research.

“That’s very difficult to do, and it’s rare to obtain” these cells from people, she said. To date, most studies of DRG neurons have been done in animals.

The study was published May 1, 2019, in the journal BRAIN.

A little background on the pain system
The DRG contains the cell bodies of sensory neurons. Cell bodies are structures that contain the nucleus of the cell. The DRG neurons are clustered together outside the spinal cord, and each neuron in the DRG extends a long process called an axon that branches out to form nerve endings in the skin and other parts of the body.

Painful stimuli—touching a hand to a hot stove, for instance—will trigger nerve endings in the skin to “fire” an electrical signal that travels along the axon into the DRG. The DRG then relays the signal into the spinal cord, where it eventually makes its way up to the brain.

But the neurons in the DRG don’t all extend to the same places in the body. Rather, they “map” onto particular areas of the skin known as dermatomes. Each DRG thus corresponds to a certain skin region and is responsible for sensations coming from that region.

When being spontaneous isn’t a good thing
In the new study, the patients who donated DRG samples for the research each came along with a detailed medical history. Because patients were affected differently by their tumors, the investigators could look at neurons from a DRG that corresponded to dermatomes where the patients had neuropathic pain, and then compare them with neurons connected to dermatomes without pain, sometimes even in a single patient.

“To have that unique opportunity to get a ganglion from one dermatome that’s affected and another that is not—it lets you cancel out all the rest of the patient’s medical history, which is pretty cool,” Dougherty said.

The researchers grew individual sensory neurons from the DRGs in a lab dish and recorded the electrical activity of the cells, a technique known as electrophysiology. The recordings showed that neurons from ganglia [ganglia is the plural form of ganglion] that served dermatomes with neuropathic pain—but not those without it—fired spontaneously. That is, they needed no incoming stimulus to fire.

“It was the first thing we looked for, and it jumped right out,” recalled Dougherty of the spontaneous activity. “It seems to be fundamentally important.” And, Dougherty said, “the activity just doesn’t appear when there was no pain” associated with the dermatome.

In fact, although the researcher making the recordings did not know whether each ganglion corresponded to a painful or non-painful dermatome, “you can almost tell right away what dermatome they came from” based on their activity, according to Dougherty.

About one in five DRG neurons with corresponding pain in a dermatome displayed spontaneous firing, whereas neurons without dermatomal pain only rarely did.

As in animals, as in people
The idea that ectopic activity in sensory neurons might underlie neuropathic pain is not a new one. In fact, it arose from animal studies and was first put forth three decades ago by Patrick Wall and Marshall Devor, who termed the activity “ectopic.”

“The word ‘ectopic’—it means ‘coming from the wrong place,’ so instead of originating at sensory [nerve] endings, signals arise from a nerve injury site or at the DRG itself,” said Devor, Hebrew University of Jerusalem, Israel, who was not involved in the current study.

Neuropathic pain can be caused by any of a whole list of possible culprits: diabetes, chemotherapy, viruses and tumors, to name but a few. Regardless of its cause, chronic neuropathic pain has been likened to a fire alarm that won’t stop jangling. But researchers have debated what drives that alarm. Is it because of the activity pain-sensing neurons in the peripheral nervous system (outside of the brain and spinal cord)? Or does the pain depend on activity within the brain?

In 2014, Devor and colleagues performed an experiment with patients suffering from phantom limb pain (PLP), a type of neuropathic pain that affects amputees. PLP was thought by most researchers to arise from changes in the cortex, the outermost layer of the brain where higher processing of pain takes place.

Devor showed, however, that application of a local anesthetic directly onto the DRG halted PLP in the patients. This indicated that the peripheral nervous system was driving the neuropathic pain. But researchers still didn’t know how.

The current study provides an explanation, showing that human neurons affected by chronic pain are spontaneously active, just as is the case in animals. “We think that our paper, the electrophysiology, is the first evidence that this firing definitively happens in people,” said Price.

Devor said while he was not surprised by the finding of ectopic activity in the neurons.

“I’m pleased of course to know the same thing happens in humans. The ectopic firing that we’re familiar with—its presence in ganglia with pain and not in ganglia without pain—that’s impressive.”

Denk thinks the observations should be exciting to patients, because “we can actually observe the dysfunction. This hypersensitivity driving pain—we can measure it. You can see that the neuron behaves differently. It’s a real thing in these neurons, and it’s a real thing in people with chronic pain as well,” she said.

This story first appeared on the Pain Research Forum and has been adapted for RELIEF. 

Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD

Image credit: Rostislav Zatonskiy/123RF Stock Photo.