Compared to other areas of the body, the fingertips are especially sensitive to the threat of an injury. And yet, they possess fewer neurons that transmit pain signals. Now, new research led by Wenqin Luo at the University of Pennsylvania in Philadelphia hints that the keenness of pain—so-called pain acuity—might be tied to the shape of nerve fibers in the spinal cord.
Thanks to a new line of genetically altered mice, Luo and her colleagues closely examined the structure of one class of pain neurons. Like other neurons in the peripheral nervous system (that is, outside of the brain and spinal cord), these cells have nerve fibers that begin in the body and end in the spinal cord. But they are also unique in that they contain a protein called Mrgprd, and send pain signals from only one tissue in the body—the skin.
Across different skin areas, nerve fibers containing Mrgprd did not vary in size or shape. In the spinal cord, however, Mrgprd nerve fibers coming from the animals’ paw skin had a round shape, while those coming from a different region, the skin of the trunk, were long and thin. Consistent with these differences, the researchers found that paw nerve fibers needed less stimulation to trigger pain-related behaviors in the mice.
“The images and findings in this study are stunning,” says Mark Zylka, a neuroscientist at the University of North Carolina in Chapel Hill who was not involved in the research.
Xinzhong Dong, a pain researcher at Johns Hopkins University in Baltimore who also did not take part in the new work, says the findings contrast the keenness of pain with that for touch, since touch does in fact rely on a high density of nerve fibers in the skin.
The findings were published online October 12, 2017 in the journal eLife.
In 2013, Luo’s lab used genetically modified mice to study how neurons that sense either touch or movement formed branches in the spinal cord. Out of this work grew the idea to also trace the paths of pain neurons.
So lead author William Olson and colleagues engineered mice with Mrgprd nerve fibers that could be visualized in the skin or spinal cord. Similar to what’s seen in people, there was not a greater density of these fibers in the animals’ paw skin, relative to to their trunk skin, nor did the fibers have a dramatically different shape. In contrast, when looking in the spinal cord, the researchers saw that the branches of the fibers looked either round, or long and thin.
Without a clear idea of what this showed, the researchers knew of a study from another research group that found that people could localize pain better on their fingertips than on the back of their hands. And, they could do so despite the fact that the fingertips had a lower density of nerve fibers.
“It provided a new angle of thinking for us,” says Luo. “It made us wonder, ‘Could the phenomenon we see here explain pain acuity?’”
Indeed, the location of the round and long/thin branches in the spinal cord suggested they belonged to paw or trunk skin nerve fibers, respectively. Perhaps, the researchers thought, these differences in shape could help explain why some areas of the body, like the fingertips, are more sensitive to pain.
To test this idea, the scientists examined pain-related responses of the genetically altered mice. The animals withdrew their paws when the Mrgprd fibers in these regions were experimentally activated with light (a technique called optogenetics that is commonly used in neuroscience to understand how the nervous system controls different behaviors; see RELIEF related content here). But for fibers higher up on the leg, this manipulation had no effect. Only when the light stimulation was increased by at least twofold did the animals respond.
To Luo, this might mean that signals carried by pain neurons in specific parts of the body, such as the paw, become amplified after they reach the spinal cord or brain. As a result, the nervous system could gather more information about a potential injury, without having to rely on a higher density of nerve fibers in the skin.
As for how such amplification occurs, Luo can only speculate. For instance, the round branches may form more connections with neurons in the spinal cord, she says.
To read about the research in more detail, see the related IASP Pain Research Forum news story here.
Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman