Newly discovered pain pathway may help explain why animal tests fail to reveal the best painkillers

If you’ve ever unwittingly grabbed a hot pan, you know our bodies have exquisite reflexes for avoiding or minimizing injuries. But once the damage is done, we also have a spontaneous urge to sooth the pain—to blow on a burned hand, cradle a broken toe, or suck on a cut finger. A new study reveals a neural circuit behind this soothing response in mice. Many common animal tests of pain don’t involve this circuit, the authors contend, which could explain why some painkillers that seem to work in mice prove ineffective in people.

“We know there is not just one ‘pain pathway’ or a single brain site involved in processing pain,” says Kathleen Sluka, a neuroscientist at the University of Iowa in Iowa City, who was not involved in the new work. “Understanding the different pathways that underlie unique behaviors could one day help us to individualize treatments” for patients based on how they respond to pain.

Harvard University neurobiologist Qiufu Ma and his team wanted to tease apart different aspects of pain, not just in the brain but in the neurons throughout our bodies that relay signals up the spinal cord. Ma and his collaborators previously proposed two general groups of sensory neurons: ones that project to the outermost layer of skin and ones that branch to deeper tissue throughout the body—the underlying skin layers, bones, joints, and muscles. Ma suggests the first group is a first-line defense that monitors our surroundings for danger and prompts us to pull away from a hot pan or a sharp prick. The deeper nerves, he suggests, are attuned to the lasting pain of an injury or illness—and may drive the experience of unpleasantness and distress that comes with pain. Our reflexes avoid potential harm, Ma explains; “the suffering of pain is very different.”

In the new experiment, Ma and his collaborators characterized a set of neurons that seem to underlie this second type of experience. They created mice that lack a particular type of excitatory spinal cord neuron marked by its expression of a gene called TAC1. These mice still had reflexes, quickly pulling back their paws when pricked, for example. But in tests involving prolonged, inescapable pain, the mice were unique. Unlike control mice, they didn’t nurse their wounds, licking their paws obsessively when they were burned, injected with mustard oil, or pinched by a metal clip that they couldn’t remove. Thus, the researchers conclude that TAC1 neurons are uniquely involved in “coping” with ongoing pain, they write today in Nature .

They also found a set of neurons in the skin that drives that prolonged painful experience. These neurons, known as TRPV1 neurons, seem to pass their signal to TAC1 spinal cord neurons, which project to the medial thalamic nucleus, a key sensory relay station at the base of the brain.

To Ma, the mouse findings represent alarming evidence of a blind spot in pain research. Many common tests of animal pain measure a defensive reflex—for example, how long it takes to pull back a paw that’s been poked. These tests are standardized and precise, Ma says, but they may activate only superficial nerve fibers—not the TAC1 pathway that leads to ongoing pain. New pain drugs should be tested for how they affect this coping response in animals, Ma says. And the ideal pain drug would selectively target the newly identified pathway.

The new paper is a “really insightful” look at what drives the emotional side of pain, says Gregory Dussor, a neurobiologist at the University of Texas in Dallas. But because the pain tests in the study last only a few minutes, he says, it’s still not clear what role TAC1 and TRPV1 neurons play in chronic pain—a huge source of human suffering. The limitations of reflex-based animal tests are well known, he says, but “I think it’s still a little too early to say that this is [the pathway] we need to be looking at” in the search for new drugs.

Dussor and other researchers are also uneasy with the claim that the newly identified neurons really drive a coping response in mice. “I understand the vocabulary is limited for describing what a licking response might actually reflect,” says Kathryn Albers, a neurobiologist at the University of Pittsburgh in Pennsylvania. “But ‘coping’ might be a stretch.”

Ma says he and his colleagues agonized over word choice. And they did find parallels between the licking behavior in mice and subjective pain ratings from people given a painful pinch test—the time spent licking and the perceived pain intensity seemed to peak and plateau in unison as the pinch wore on. In this field, the potential mismatch between animal and human pain always looms. “How can little mice tell us what they feel?” he says. “It’s forever a challenge.”