One Step Closer to Understanding the Placebo Effect in Pain Treatment

Proven Placebo Effect

That the placebo effect works is evidenced by real life and double-blind randomized clinical trials. However, its principle is not yet fully understood. Researchers from the University of North Carolina at Chapel Hill and colleagues from several other American universities have discovered a pain control pathway that connects the rostral region of the anterior cingulate cortex through the pons in the brainstem to the cerebellum.

Understanding the biological basis of pain relief in placebo analgesia—when positive patient expectations alone are enough to feel better—comes, according to the authors, from brain imaging studies. However, these studies were not precise enough to reveal what is actually happening in these brain areas. The research team used an animal model, specifically mice.

Behavioral Pain Test in Mice

Their work involved behavioral testing of mice that expected pain relief (as with a placebo) and subsequently experienced it (as in the placebo effect). The researchers emphasize that placebo effects clearly demonstrate the close interaction between the mind and body.

In the study, they used various techniques—genetic neuron labeling, calcium imaging in freely behaving mice neurons, single-cell RNA sequencing, electrophysiological recordings, and optogenetic methods. This allowed them to study the complex neurobiology of the placebo effect down to brain circuits, neurons, and synapses across the brain.

Learned Expectation of Analgesic Effect

The behavioral test had three phases:

• Days 1–3: Acclimatization—in both test chambers, the floors were heated to a harmless 30°C, and the mice could freely explore them.

• Days 4–6: The floor temperature in Chamber 1 was set to 48°C (harmfully hot), while in Chamber 2 it remained at 30°C. This taught the mice to expect pain relief when leaving Chamber 1 and entering Chamber 2.

• Day 7: The test—the floors in both chambers were heated to 48°C, and researchers assessed whether an analgesic effect triggered by the expectation of pain relief occurred.

It turned out that even when both chamber floors were hot, mice preferred Chamber 2, where the floor had previously been cooler. Additionally, their reluctance to revisit Chamber 1 increased, even on the day when both floors were equally hot. When the researchers later reduced the floor temperature in both chambers back to 30°C, the mice’s preference for Chamber 2 disappeared.

Cortico-Ponto-Cerebellar Pathway

The team also discovered that when the mice expected pain relief, neurons in the rostral anterior cingulate cortex, previously associated with the placebo effect, sent signals to the nucleus pontis in the pons. This brain region had not yet been assigned a role in pain perception or relief. The expectation of pain relief manifested in signals along this pathway.

The researchers pointed out that this pathway contains an exceptionally high number of opioid receptors. By suppressing activity along this pathway, they disrupted placebo analgesia and lowered the pain threshold. Conversely, activating it induced pain relief even without a placebo.

Finally, they found that activity patterns similar to those observed in anterior cingulate cortex neurons during the expectation of pain relief were also exhibited by Purkinje cells in the cerebellum. In other words, the cerebellum likely plays a role in the cognitive modulation of pain perception. The published study thus describes a cortico-ponto-cerebellar pathway.

Potential Applications in Humans

The authors emphasized that administering an opioid receptor antagonist during the final test (Day 7) abolished the placebo analgesic effect. According to them, this aligns with the known involvement of endogenous opioid signaling in placebo analgesia in humans. The observed analgesic effect based on the expectation of pain relief shares key features with placebo analgesia in humans, which, according to the authors, enables the modeling and study of placebo analgesia in rodents.

“We all know that we need better treatments for chronic pain, especially treatments without side effects and addiction potential. We believe that our findings open the door to focusing on this new pathway so that people can be treated differently but potentially more effectively,” stated study co-author Dr. Grégory Scherrer.

Editorial Team, Medscope.pro

Sources:

1. Chen C., Niehaus J. K., Dinc F. et al. Neural circuit basis of placebo pain relief. Nature 2024 Aug; 632 (8027): 1092–1100, doi: 10.1038/s41586-024-07816-z.

2. University of North Carolina Health Care. Neuroscientists discover brain circuitry of placebo effect for pain relief. ScienceDaily, 2024 Jul 24. Available at: www.sciencedaily.com/releases/2024/07/240724123119.htm