May 21, 2025 Research Highlight Biology
How the placebo effect tricks the mind into relieving pain
Scientists have determined for the first time how the placebo effect administers pain relief
Figure 1: Sometimes merely taking a pill that you believe is a painkiller is enough to bring pain relief, even if it has no pharmaceutical effect. RIKEN researchers have determined the detailed neural mechanism behind the placebo effect. © Alla Bielikova/Moment/Getty
The detailed mechanism of how the placebo effect reduces the perception of pain in rats has been uncovered by RIKEN neuroscientists1. This finding could potentially lead to ways to harness the placebo effect in therapy.
If you’re convinced you are taking a powerful painkiller, it could well reduce your perception of pain, even if the painkiller turns out to be a sham.
That’s the power of the placebo effect. The brain, tricked into anticipating a benefit, produces the benefit itself.
Harnessing the placebo effect for pain relief could help to reduce dosages of painkillers, lowering the risk of both side effects and becoming dependent on medication.
Because it’s a psychological effect, the placebo effect is much easier to induce and monitor in humans than in animals. But since only relatively non-invasive techniques can be used on people, it’s hard to determine what’s happening on a neural-circuit level.
“Ethical concerns and technical limitations make it impossible to determine what neurons and circuits are involved in the placebo effect in people,” notes Yilong Cui of the RIKEN Center for Integrative Medical Sciences. “But we could ascertain a more detailed mechanism, if we could induce the placebo effect in animals.”
That’s what Cui and co-workers did—they conditioned rats by injecting them with a painkiller over four days. The animal came to associate injections with pain relief, so that when they were injected with a saline solution, the placebo effect kicked in.
“Many researchers didn’t believe that animals could experience the placebo effect,” says Cui. “But we succeeded in inducing it in rodents by using Pavlovian conditioning.”
About a third of the rats exhibited the full placebo effect, another third had a partial placebo effect, and the remaining third hardly experienced any pain relief.
Cui’s team was then able to study what was going on in the animal brains using neuroimaging methods that are too invasive to use on people.
Several brain regions were found to activate in response to placebo in neuropathic animals. “That’s very similar to results in humans,” Cui says.
“We were able to identify a very detailed mechanism on a single-channel level,” says Cui.
The team found that the placebo effect occurred as a result of brain signals related to the endogenous opioid system in the medial prefrontal cortex, a region at the front of the brain, which in the presence of the placebo injections set off the descending pain inhibitory system.
They strongly suspect that the same mechanism operates in people. “The mechanism is similar to how pain relief occurs in humans,” notes Cui.
Cui’s team is now trying to trace the mechanism further upstream, by investigating what triggers the opioid signals.
Hiroyuki Neyama (left), Yilong Cui (right) and their co-workers have induced placebo analgesia in rodents and found that endogenous opioids activate the descending pain inhibitory system. © 2025 RIKEN
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Reference
- 1. Neyama, H., Wu, Y., Nakaya, Y., Kato, S., Shimizu, T., Tahara, T., Shigeta, M., Inoue, M., Miyamichi, K., Matsushita, N. et al. Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia. Science Advances 11, eadp8494 (2025). doi: 10.1126/sciadv.adp8494