Placebo Effect Neural Circuits Could Explain Pain Relief

Placebos present an appealing prospect: easing pain without medicines or surgery, instead depending largely on the expectation that the pain will disappear.

Although this may seem vague and hard to pin down, the placebo effect is genuine. In a recent mouse-based experiment, scientists have linked it to particular neural circuits in the brain.

The research team, led by University of North Carolina (UNC) Chapel Hill anaesthesiologist Chong Chen, also found that a brainstem area not formerly associated with pain processing does in fact have a role in it.

The placebo effect and expectations of pain relief

For years, researchers have searched for the biological foundation of the placebo effect in the brain. This is challenging because an individual's placebo response is intertwined with psychology and may be shaped by previous experiences that condition them to think in a particular way.

Expectations about whether a treatment or operation will succeed in relieving pain are also part of the placebo effect. Doctors' authority can have considerable influence over those expectations.

Brain-imaging research has identified features believed to leave some people more responsive to the placebo effect. These include variations in the connections between the anterior cingulate cortex, the prefrontal area in front of it, and the brainstem beneath.

Such regional differences, which can be detected in brain scans, may help predict who will respond particularly strongly to a placebo and how this could influence clinical trials. However, establishing how the placebo effect develops and identifying the brain cells involved requires a closer examination.

Chen and his colleagues investigated neural circuits linked to pain relief in mice. The animals had been trained to expect that one side of a two-part chamber would be pleasantly cooler than the other, which was heated to a painful 48 °C.

Placebo treatments can measurably lessen a patient's discomfort or pain, even when patients know that the treatment is a sham, although their physiological effects can vary and be inconsistent.

This has prompted the contentious proposal that placebos might be provided openly as pain relief. Doing so could avoid the ethical problems of deceiving patients while still triggering an analgesic effect for the millions of people around the world living with chronic pain.

Yet the pain-relieving influence of placebos comes from taking part in the ritual of medicine, whether the tablet or remedy is genuine or false. That creates complications for clinical trials, as it makes it more difficult for researchers to establish whether a new drug effectively relieves pain.

It is therefore unsurprising that scientists want a clearer understanding of the mechanisms behind pain and the placebo effect, rather than relying only on a broad view of the brain regions involved.

How placebo effect circuits affected mice

In their animal studies, Chen's team found that, after several days of conditioning, mice spent longer on the floor that had previously been cooler, despite it now being heated to 48 °C as well.

The conditioned mice also showed fewer behaviours associated with pain relief, including standing upright on their hind legs and licking their feet. This indicated that they could withstand the higher temperature because a pain-relieving placebo effect had taken hold.

To identify the neural circuits that were most active in the temperature trials, the scientists equipped the mice with small microscopes mounted on their heads. They then recorded neuronal activity in the rostral anterior cingulate cortex (rACC), a region highlighted in earlier brain-imaging studies.

Brainstem pathways involved in pain tolerance

The real-time imaging showed networks linking the rACC with the pontine nuclei. These nuclei are in the pons, a brainstem region known to contribute to motor function, and the networks became active when the placebo effect occurred.

After the researchers disabled this newly identified pathway, the mice could no longer tolerate the painfully hot floor. Conversely, artificially activating the circuits produced a placebo effect in animals that had not first been conditioned to expect pain relief from the cooler floor.

Additional staining of brain tissue revealed that a "remarkably large proportion" of neurons in the pontine nuclei carry opioid receptors that regulate pain.

The finding points to a previously unrecognised role for the pontine nuclei in pain tolerance. They could potentially be stimulated or targeted using medicines, electrodes or therapies to treat pain.

First, however, researchers will need to determine how these animal-experiment results apply to humans, whose experiences of pain are much more complex.

The study has been published in Nature.