A Tiny Channel in Your Nerves May Hold the Key to Chronic Pain

Scientists have found that a tiny protein called TWIK-1 helps control how we feel touch and pain. TWIK-1 is a channel, meaning it acts like a tiny door in nerve cells that lets certain particles flow in and out. Researchers studying mice discovered that this channel works in very different ways depending on where it is in the body. Its location makes a big difference for people who suffer from long-lasting pain after a nerve injury.

The study focused on two main areas of the nervous system: the dorsal root ganglia, or DRG, and the spinal cord. The DRG is a cluster of nerve cells that sits just outside the spinal cord and sends touch and pain signals toward the brain. The spinal cord then processes those signals before they reach the brain. Both areas contain TWIK-1, but it turns out the channel does different things in each place.

Researchers first looked at where TWIK-1 shows up in the nervous system. They found it is very common in large and medium-sized nerve cells in the DRG — the cells that carry signals about light touch and gentle pressure. TWIK-1 was less common in small nerve cells that carry signals about sharp pain and burning heat. In the spinal cord, TWIK-1 appeared in many different cell types, including cells that turn signals on, cells that turn signals off, and support cells called astrocytes.

To figure out what TWIK-1 does, scientists created special mice that were missing TWIK-1 in specific parts of their bodies. When mice had no TWIK-1 anywhere, they had trouble feeling light touch. They were slower at noticing sticky tape on their paws and could not tell smooth surfaces from rough ones. They also felt less pain from moderate poking with a thin filament, but still reacted normally to very intense pain, extreme heat, and extreme cold.

The researchers then asked which part of the nervous system was responsible. When they removed TWIK-1 only from DRG nerve cells, the mice felt touch and pain completely normally. This was a big surprise. It meant that TWIK-1 in the DRG is not needed for everyday touch and pain feelings under normal conditions.

Next, the team removed TWIK-1 only from nerve cells in the spinal cord. Those mice had the same trouble with light touch and moderate pain as mice missing TWIK-1 everywhere. So the spinal cord, not the DRG, is where TWIK-1 shapes normal touch and pain. Scientists then found that only the inhibitory, or quieting, nerve cells in the spinal cord mattered — not the exciting ones.

Here is why that makes sense. TWIK-1 normally acts like a brake on nerve cells by letting potassium particles flow out, keeping the cell calm. Without TWIK-1, the inhibitory nerve cells become overactive. When inhibitory cells fire too much, they quiet down pain signals too strongly, so the animal feels less touch and moderate pain than it should.

The story takes a twist when it comes to nerve injury. Scientists damaged the sciatic nerve of mice — a common way to study chronic pain in the lab. Normal mice developed pain that lasted for weeks, keeping a hurt paw off the ground. But mice missing TWIK-1 everywhere recovered much faster, walking normally by about six weeks after injury.

Scientists found that it was TWIK-1 in the DRG nerve cells — not the spinal cord — that made the difference for chronic pain. When TWIK-1 was removed only from DRG cells, those mice also recovered quickly. But when it was removed only from spinal cord cells, the mice still had long-lasting pain. This showed that the two locations of TWIK-1 have completely opposite roles.

To understand why, scientists looked at DRG nerve cells after injury. Normally after nerve damage, DRG cells become overexcited and fire too easily — and that over-excitement keeps chronic pain going. In mice without TWIK-1 in their DRG, this over-excitement did not happen. The injured nerve cells stayed calmer and were harder to trigger, which helped pain fade away.

Scientists also studied genes after nerve injury. In normal mice, many genes changed their activity after injury, including genes involved in inflammation and potassium channels. But in mice without TWIK-1, many of these gene changes did not occur. This suggests that TWIK-1 helps set off a chain of molecular events after injury that keeps pain going for a long time.

In summary, TWIK-1 plays two very different roles. In the spinal cord's inhibitory nerve cells, it helps us feel normal levels of touch and moderate pain every day. In DRG nerve cells, it is not needed for everyday feeling, but becomes important after a nerve injury for keeping chronic pain alive. These findings could help scientists design new treatments for chronic pain that target TWIK-1 in DRG nerve cells without interfering with normal touch and pain sensing.