2024-08-03 06:08:20
Pain research has long been hampered by experimental design where even studies that are “double-blind” and randomized will still find that those given a placebo report some relief from the unknown drug. But until now, scientists didn’t know what happens in the brain when this happens.
In a study led by researchers at the University of North Carolina (UNC) School of Medicine along with researchers from Stanford, the Howard Hughes Medical Institute and the Allen Institute for Brain Science, a pathway from the cerebral cortex to the cerebellum reveals how a person can experience a reduction in pain without any analgesic intervention.
“The fact that cortical neurons communicate with the pons and cerebellum and regulate the pain threshold as we expect is completely unexpected given our previous understanding of the pain circuit and extremely exciting,” said Greg Scherrer of the UNC School of Medicine. “Our results open up the possibility of activating this pathway with other therapeutic means, such as drugs or neurostimulation techniques, to treat pain.”
Using the images, the researchers first identified areas of the brain with increased activity, but it wasn’t clear exactly what was happening—only that something was definitely happening. They then carried out a complex study in mice to find out what mechanisms were at work.
In a study in mice, the researchers found that neurons and synapses along the pathway from the forebrain through the pons to the hindbrain were highly activated when pain relief was expected, regardless of whether the actual drugs were administered.
Examining the ACC cortex, which has been linked to the placebo effect in pain studies, the researchers used several methods to unravel the mystery: genetically labeled neurons, imaging to monitor neuronal calcium levels, single-cell RNA sequencing, electrophysiological recordings, and optogenetics.
The researchers found that when the mice received a harmless dose of the drug, instead of pain relief, rostral ACC neurons signaled to a pons nucleus not previously associated with pain or pain relief—and other signals in this pathway were activated.
“There is an extraordinary abundance of opioid receptors here, which supports their role in pain modulation,” says Scherrer. – When we inhibited the activity of this pathway, we realized that we disrupted placebo analgesia and lowered the pain threshold. And then when we activated this pathway in the absence of placebo conditioning, we caused a reduction in pain.”
The researchers found that large, branch-like Purkinje cells in the cerebellum replicated the activity seen in the primary area of neuronal excitability, the ACC. This confirmed that the cerebellum plays an important role in the transmission of pain messages.
These results don’t just solve a neurological puzzle and disprove any idea that the placebo effect is “only in your head” (although, quite literally, it is). Researchers believe this could lead to new ways to treat pain (including chronic disorders) that are difficult to treat effectively.
“We all know that we need better ways to treat chronic pain, especially treatments that don’t have harmful side effects and addictive properties,” says Scherrer. “We think our results open the door to this new neural pathway for pain, so that people can be treated in a different, but perhaps more effective, way.”
The study is published in the journal Nature.
Adapted from New Atlas.
2024-08-03 06:08:20