Why pain sometimes lingers
Animals have nerves that can make a soft caress painful.
A once-mysterious neural pathway may have a crucial role in making injured areas overly sensitive to touch, a study in mice suggests.
When a person has any kind of injury — a broken shin, for example, or a sunburn — the pain system becomes hypersensitized, firing up in response to normally painless sensations induced by, for instance, walking or a gentle massage. Normally, this tenderness protects the vulnerable tissue as it heals. But occasionally the pain can overstay its usefulness, becoming chronic in conditions such as arthritis.
Now, neuroscientists Robert Edwards and Allan Basbaum from the University of California, San Francisco, and their colleagues have found that a small subset of nerve fibres, the function of which remained a puzzle since their discovery decades ago1, could be routing innocuous touch sensations to the pain pathway when there's an injury.
"Surprise would be an understatement," says Basbaum, referring to the findings. "No one knew anything about what these fibres were doing."
The team's findings are published by Nature2.
The researchers found that the fibres, called unmyelinated low-threshold mechanoreceptors (C-LTMRs), are easily stimulated, unlike classic pain fibres, which respond only when the sensation is intense. But C-LTMRs aren't usually used to detect light touch — this falls to another another major group of sensory neurons — so their role was unclear. The small population of cells have remained enigmatic because they have been difficult to target specifically.
The authors cleared that hurdle when they discovered that these fibres express VGLUT3, a protein necessary for the cells to send signals to other neurons. Because all of the other sensory neurons going to the spinal cord use a different protein — VGLUT1 or VGLUT2 — the authors could engineer mice lacking VGLUT3 to render all the C-LTMRs silent.
Mice without functional C-LTMRs responded in exactly the same way as normal mice when exposed to light touch and to most painful stimuli, including extreme cold or heat or being poked in the paw with thin wires. But then the authors tested how the mice responded after being injured in three other ways: by a chemical that causes inflammation, which occurs in situations ranging from muscle injuries to a misaligned back; an incision, mimicking pain after surgery; and nerve damage.
In all three types of injury, normal mice became much more sensitive to wires poking their paws, quickly flicking the wires away. But mice with silent C-LTMRs showed much the same responses as before they were injured. All mice, however, became more sensitive to heat, suggesting that the C-LTMRs were hypersensitizing the animals to touch rather than to temperature.
There was one type of pain that, without injury, the engineered mice were less sensitive to than normal mice: intense, persistent pain, such as that caused by a clip pinching the tail. The finding seems contradictory, because C-LTMRs are easily stimulated. One possibility is that a small minority of neurons with VGLUT3 respond to pain, Basbaum says.
Paths to pain
Before this study, researchers had demonstrated two ways for animals to become hypersensitive after injury. First, sensory fibres can become more sensitive to stimulation; this is thought to lead to temperature hypersensitization, as happens when sunburn makes a warm shower feel excruciatingly hot. Second, another set of fibres that, like C-LTMRs, have a low threshold and are important for detecting light touch, are believed to be recruited into the spinal cord's pain circuit — any sensation they transmit is then perceived as painful.
"This paper says hold on, there's a whole other population. It's another circuit, a potential target from a clinical perspective," says Basbaum. Basbaum thinks that injury also leads to these fibres' recruitment into the pain circuitry; they may work with the other low-threshold touch fibres or be important for hypersensitivity to different stimuli.
"We knew these fibres existed, but their function was not at all clear until now," says neuroscientist Clifford Woolf at Harvard Medical School in Boston, Massachusetts. "The data show that recruitment of these fibres is a new way of producing mechanical hypersensitivity. It's an exciting example of the specific functions of different sets of sensory neurons."
- Bessou, P. & Perl, E. R. J. Neurophysiology 32, 1025-1043 (1969).
- Seal, R. P. et al. Nature advance online publication doi:10.1038/nature08505 (2009).