The placebo effect can be surprisingly effective in helping against pain because it is more than just a psychological effect: the mere expectation of an effective treatment causes the body’s own opioids to be released. However, the mechanisms by which this works were previously unclear. Researchers have now decoded the neural circuits involved in mice. The results could help to specifically activate the placebo effect in the future and use it as a natural method of pain relief.
The placebo effect ensures that many complaints improve simply because of our expectations – even if we only receive a fictitious treatment. This effect is particularly powerful when it comes to pain: Previous studies have shown that medications without any active ingredients can relieve pain to a similar extent as highly effective opioids if the test subjects expect a corresponding effect. Even with real medications, the placebo effect can increase the effect.
This is more than just our imagination: in anticipation of pain relief, our body releases endorphins, i.e. the body’s own opioids. Even if the test subjects know that they are only receiving a sham treatment, the effect can take effect – albeit in a weaker form. In previous studies, targeted conditioning has also proven to be helpful in reliably producing a pain-relieving placebo effect in people. However, it was still unclear which neural mechanisms were behind this.
Pain test with mice
In order to track down the processes in the brain, a team led by Giulia Livrizzi from the University of California in San Diego carried out a series of experiments with mice. “We essentially trained a mouse brain to produce its own broad-spectrum painkillers on demand, exactly where they are needed to treat pain, without the unwanted effects of opioid-based painkillers,” says Livrizzi’s colleague Janie Chang-Weinberg.
For their experiment, the researchers repeatedly placed mice on a hot plate and observed how quickly they began to lift their paws, shake them, lick them or jump into the air in pain. To condition the animals, they gave them the painkiller morphine before every other run and placed them in a room with polka dot walls and a citrus scent. The animals learned that they could expect less pain after staying in this room.
The body’s own opioids thanks to conditioning
In fact, the conditioning resulted in a clear placebo effect: When the mice trained in this way came into the dotted citrus-scented room and then onto the hot plate without painkillers, they twitched their paws back much later and jumped into the air less often – almost as if they had previously received morphine. “The extent of placebo pain relief was around 30 to 60 percent of the morphine effect,” report the researchers. This applied not only to the heat pain with which the mice had been conditioned, but also to other types of pain, such as injuries or inflammation on the paws. Even after several runs without painkillers, the conditioning only decreased slowly. The placebo effect thus proved to be stable over the long term.
Another test showed that the effect was really based on the body’s own opioids: When the researchers gave the mice the drug naloxone, which blocks opioid receptors, the placebo pain relief was completely absent. Additional analyzes revealed the brain region responsible: The crucial factor is signal transmission in the so-called ventrolateral periaqueductal gray (vlPAG). This region forms a kind of switching point between signals from the cerebrum, the brainstem and the spinal cord and has previously been linked to pain processing. In this region of the brain, injected opioids have their effect and it is precisely here that the body’s own endorphins are released due to the placebo effect.
From the researchers’ perspective, this newly gained mechanistic understanding can help to use the placebo effect more specifically for pain relief in humans in the future. “Placebo training could be used in people to develop resilience to future pain – whether it is expected pain, such as from an upcoming surgery, or unexpected pain, such as from a broken bone after a fall,” says Livrizzi’s colleague Matthew Banghart. A targeted placebo effect could possibly help to reduce the use of addictive opioid painkillers.
Source: Giulia Livrizzi (University of California, San Diego, USA) et al., Neuron, doi: 10.1016/j.neuron.2026.03.025