NCCIH Researchers Describe Specialized Neurons That Play a Unique Role in Mechanical Pain

Researchers at the National Institutes of Health (NIH) have identified a class of sensory neurons (nerve cells that receive and send messages between the body and brain, by electrical current) in mice that can be activated by stimuli as precise as the pulling of a single hair. These new findings were published recently in the journal Neuron.

Scientists know that distinct types of neurons detect different types of sensations (touch, heat, cold, pain, pressure, and vibration). But they know more about neurons involved with temperature and touch than those underlying mechanical pain (i.e., anatomical pain brought on or relieved by specific postures or activities). In this study, a team of researchers led by the National Center for Complementary and Integrative Health used a novel strategy that combined functional imaging (which measures neuronal activity), recordings of electrical activity in the brain, and genetics to see how neurons respond to various stimuli. The scientists focused on a class of sensory neurons that express a gene called Calca (which directs the production of a neuropeptide called CGRP, or calcitonin gene-related peptide) since these neurons have a long history in pain research.

During their research, the scientists applied various stimuli to the hairy skin of the animals’ cheeks, including gentle mechanical stimuli (air puff, stroking, and brushing), “high-threshold” mechanical stimuli (e.g., hair pulling and skin pinching), and temperature stimulation. They found that the target neurons fell into two broad categories, and both were insensitive to gentle stimulation. The first was a well-known type of pain fiber called a polymodal nociceptor that responds to a host of high-intensity stimuli such as heat and pinching. Surprisingly, they also observed a second, unique type of neuron that responded robustly to hair pulling.

They called this previously undescribed class “circ-HTMRs,” due to the unusual nerve terminals these neurons made in skin. They found the endings of fibers made lasso-like structures around the base of each hair follicle.

The researchers conducted additional experiments to learn more about circ-HTMRs, including showing that their direct activation (using a technique called optogenetics) was sufficient to drive protective behaviors, for example avoiding a chamber paired with stimulation of these neurons via blue light. One interesting feature of these neurons is that they have large spatially organized receptive fields yet can be activated by pulling a single hair. Their electrical properties enable them to signal much more rapidly than normal pain fibers and to keep firing as long as the hair is being pulled.

Overall, the researchers concluded that their findings add insight into how the somatosensory system encodes pain. Learning more about the distinctive features of circ-HTMRs could contribute to rapid, accurate localization of brain regions activated in mechanical pain and ultimately to the rational design of new approaches to pain therapy.