Nearly everyone is familiar with the feeling of accidentally touching a hot vessel or holding onto something freezing for too long. Normally, pain serves to protect from potential harm, but when the feeling of pain remains even in the absence of harmful stimuli, it can be both physically and psychologically detrimental to an individual.¹

For instance, lower back and neck pain have been among the top 10 leading causes of disability globally since 1990, but researchers still do not fully understand the mechanisms underlying pain.² In results presented at the Society for Neuroscience conference in October 2024, scientists shed light on neurophysiological pathways of pain and potential treatment avenues.

“These studies advance the understanding of both pain mechanisms and the complex manner in which humans seek pain relief that will aid in the development of novel, effective, and safer therapeutic approaches,” Gregory Dussor, a neuroscientist at the University of Texas at Dallas who was not associated with the studies, said during a press conference.

Safe drugs are especially important since people often rely on compounds like opioids—that can cause drug use disorders—for relieving pain. “[Chronic pain] is one of those conditions that can push someone to engage in ways to cope with pain that might be harmful,” said Nasim Maleki, a psychiatry researcher at Harvard Medical School. One such coping mechanism is polysubstance use—the use of multiple compounds such as opiates, cocaine, marijuana, or methamphetamine—which can eventually result in people becoming dependent on these drugs. Treating people suffering from chronic pain and a polysubstance use disorder requires a specialized healthcare approach.

To determine whether chronic pain increases the likelihood of polysubstance use, Maleki and her team assessed data from a national survey conducted in the US. They found that people suffering from chronic pain were more than twice as likely to use multiple substances than pain-free people, with this likelihood tripling among men. Data revealed that depression increased the probability of this behavior.

“We need drugs that don’t cause more problems than they are trying to fix,” said Dussor. At the same time, for approval by the Food and Drug Administration, these drugs must outperform placebo treatments that have no active properties but can still lessen pain. Despite the power of the placebo effect, the exact biological pathways behind the phenomenon remained incompletely understood. “So, all new drugs are up against a mechanism that we don’t fully understand,” said Dussor.

In a recent study, Grégory Scherrer, a neurobiologist at the University of North Carolina at Chapel Hill and his team uncovered brain circuits in mice that are involved in the placebo effect.³ They designed behavioral experiments to induce a placebo-like expectation of pain relief in mice and traced the brain areas activated in these animals. They observed neuronal activity in a part of the brainstem that connects the cerebral cortex and cerebellum, an area that has not been associated with pain previously.

In addition to revealing the neurons that mediate the placebo effect, these experiments identified new brain circuits that can modulate pain perception, said Scherrer. “So, we can now target these circuits either with novel drugs or with neurostimulation techniques to develop treatments for pain.”

Aside from the challenges of beating the placebo effect, drugs do not always work on pain caused by different insults—like stubbing a toe, a pin prick, hair pulling, or a pinch. While people can easily distinguish between these stimuli, researchers do not completely understand the neural mechanisms behind how the nervous system tells the difference.

Now, Emma Kindström, a neuroscientist at Linköping University, and her colleagues have demonstrated that PIEZO2—a receptor that converts mechanical stimuli into neural signals—mediates hair-pulling pain in mice and humans. A hair-pull signal moves along ultra-fast sensory neurons at a speed of about 100 miles an hour. In contrast, other painful signals, like those induced by a pinprick, move at a speed of four miles an hour.

“[These results] provide a solid foundation for further exploration to map out additional types of pain-sensing cells, which may lead to new ways to approach and eventually to treat pain,” said Kindström.

Outperforming placebos and identifying the types of pain that a drug can treat are not the only challenges that researchers developing pain-relieving therapeutics face. “The development of new pain drugs has been hampered by the low success rate in clinical trials which is only two percent,” said Tony Oosterveen, a scientist at bit.bio. This is in part because pain researchers use animal models that do not completely capture human physiology, he explained.

To overcome this problem, Oosterveen and his team developed a technology to convert human pluripotent stem cells into sensory neurons. Their method improves upon conventional approaches—which take weeks to differentiate a fraction of the stem cells into neurons—by coaxing all the stem cells to become sensory neurons within days. Using calcium imaging experiments, the team showed that these cells respond to pain stimuli such as noxious heat or cold, offering these as a potential model to study human pain and screen drugs.

Despite these advances, pain remains a hard nut to crack. One of the reasons is that there are redundant mechanisms that ensure pain is signaled, said Dussor. “[Pain] is essential for survival. It’s one of the most essential processes that the body has to deal with.”