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The Placebo Effect Unlocked: How The Brain Tricks Itself Into Pain Relief

In a fascinating discovery, scientists have pinpointed what happens in our brains when we're expecting pain relief but are given a placebo, unknowingly, instead. It not only confirms 'the placebo effect,' but offers clues into how powerful the mind is in mitigating physiological functions such as pain.

Pain research has long been hampered by experiment design, in which even trials that are double-blinded and randomized will still see those who receive placebo treatment reporting some relief from their unknown medication. But until now, scientists haven't really known just what is happening in the brain when this occurs.

In a study led by researchers from the University of North Carolina (UNC) School of Medicine, along with Stanford, the Howard Hughes Medical Institute and the Allen Institute for Brain Science, a pathway that travels from the cortex to the cerebellum reveals just how an individual may feel pain relief without any analgesic intervention.

"That neurons in our cerebral cortex communicate with the pons and cerebellum to adjust pain thresholds based on our expectations is both completely unexpected, given our previous understanding of the pain circuitry, and incredibly exciting," said Greg Scherrer, from the UNC School of Medicine. "Our results do open the possibility of activating this pathway through other therapeutic means, such as drugs or neurostimulation methods to treat pain."

The researchers first identified, through imaging, regions of the brain that had a boost of activity, but it wasn't clear exactly what was happening – just that something was definitely happening. From here, they undertook an intricate study on mice to home in on the mechanisms at play.

In that mouse study, the researchers found that along the pathway, from the front of the brain, through the pons region of the brainstem to the cerebellum at the rear, neurons and synapses became very active when pain-relief was anticipated, regardless of whether any real medicine was then taken.

Along the 'placebo pathway', the cells in yellow in the pons (left) receive input from the green cells in the cingulate cortex (rACC, right), with subdivisions Cg1 and Cg2

Scherrer Lab, UNC School of Medicine

Looking at the anterior cingulate cortex (ACC), which has been linked to the placebo effect in pain studies, the scientists used a suite of methods to unravel the mystery: genetically tagged neurons, imaging to view calcium in neurons, single-cell RNA sequencing techniques, electrophysiological recordings and optogenetics.

What they found was that when mice received an innocuous dose of medicine, instead of pain relief, the rostral ACC neurons signaled to the pontine nucleus – which has no prior link to pain or pain relief – and along the pathway other signals had been activated.

"There is an extraordinary abundance of opioid receptors here, supporting a role in pain modulation," Scherrer said. "When we inhibited activity in this pathway, we realized we were disrupting placebo analgesia and decreasing pain thresholds. And then, in the absence of placebo conditioning, when we activated this pathway, we caused pain relief."

They found that the large, branch-like Purkinje cells in the cerebellum replicated the activity seen in the initial area of neuronal excitement, in the ACC. It confirmed that the cerebellum had a key part to play in pain messaging.

The findings do more than just solve a puzzle for neuroscientists and put to bed any thought that the placebo effect was 'all in your head' (even though, quite literally, it is). The researchers believe it has the potential for new approaches to pain relief, including chronic disorders, which have proven challenging to treat effectively.

"We all know we need better ways to treat chronic pain, particularly treatments without harmful side effects and addictive properties," Scherrer said. "We think our findings open the door to targeting this novel neural pain pathway to treat people in a different but potentially more effective way."

The study was published in the journal Nature.

Source: University of North Carolina School of Medicine

We May Finally Know How The Placebo Effect Relieves Pain

A section of a mouse brain viewed on a slide

Stu Gray / Alamy

A newly identified brain pathway in mice could explain why placebos, or interventions designed to have no therapeutic effect, still relieve pain. Developing drugs that target this pathway may lead to safer alternatives to pain medications like opioids.

If someone unknowingly takes a sugar pill instead of a pain reliever, they still feel better. This placebo effect is a well-known phenomenon in which people's expectations lessen their symptoms, even without effective treatment. "Our brain, on its own, is sort of able to fix the pain problem based on the expectation that a medication or treatment might work," says Grégory Scherrer at the University of North Carolina at Chapel Hill.

The neuroscientist harnessing the placebo effect to help soothe pain

To understand how the brain does this, Scherrer and his colleagues replicated the placebo effect in 10 mice using a cage with two chambers. One chamber had a burning hot floor, while the other didn't. After three days, the animals learned to associate the second chamber with pain relief.

The researchers then injected the rodents' brains with a molecule that causes active neurons to glow when viewed under a microscope. They placed the mice back into the cage – but this time heated both floors.

Although the chambers were now equally hot, the animals still preferred the second one, displaying fewer pain symptoms such as paw licking while there. They also had greater activity in neurons in the cingulate cortex – a brain region involved in pain processing – compared with nine mice that weren't conditioned to associate the second chamber with pain relief.

Further experiments revealed a pathway connecting these pain-processing neurons to cells in the pontine nuclei and cerebellum – two brain areas with no previous known role in relieving pain.

To confirm this circuit relieves pain, the researchers used a technique called optogenetics, which turn cells on and off with light. This let them activate the newly discovered neural pathway in a separate group of mice placed on a hot floor. On average, these animals waited three times as long before licking their paws as those that didn't have the circuit activated, indicating they felt less pain.

If this neural pathway does explain the placebo effect, "that can open new strategies for drug development", says Luana Colloca at the University of Maryland, who wasn't involved in the study. "If we have drugs that activate placebo effects, that will be a wonderful strategy for pain management," she says.

"The obvious caveat is that the placebo experience in humans is obviously much more complex [than in animals]," says Scherrer. However, he still believes these findings will translate to people because rodents and humans have very similar pain pathways.

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RimWorld Drugs And Medicine List

Drugs and medicine in RimWorld are similar in that your colonists can take them for a boost to their stats and health respectively, but where one is simply a cure for illness and injuries, the other is an optional buff that can cause addiction. Both can either be crafted at a drug lab, bought from traders, or looted from raiders, and below is a full list of all the drugs and medicine in the game.

Drugs come in three categories: Social, Hard, and Medical. Colonists cannot overdose on social drugs and while they can cause addictions, this only happens if they're taken far too often. Hard drugs, on the other hand, are much more likely to cause addictions and overdoses. Medical drugs do neither and are instead uses to treat illnesses. Here are all of the drugs in RimWorld:

Drug Category Effects Ambrosia Social Essentially a food replacement. +0.2 nutrition, +5 mood. Beer Social The more a colonist drinks, the more drunk they get. +10 mood when tipsy, +24 mood when hammered. Debuffs to consciousness, moving, and an increase chance of starting social fights. Also gies +0.08 nutrition. Flake Hard +35 mood, x33% sleep fall rate, x50% pain. Go-Juice Hard +5 mood, +20% consciousness, +50% moving, +35% sight, x10% pain. Luciferium Medical Cures one scar or chronic illness every 15-30 days. +10% consciousness, +5% moving, +15% sight, x80% pain, +70% blood filtration, +20% digestion, +15% blood pumping. Penoxycyline Medical Prevents malaria, plague, and sleeping sickness. Psychite Tea Social +12 mood, x80% sleep fall rate, x90% pain. Smokeleaf Social +13 mood, -30% consciousness, -10% moving, +30% hunger, -20% pain. Wake-Up Hard +5 mood, x80% sleep fall rate, +10% consciousness, +10% moving, +50% global work speed, increases chance of heart attacks. Yayo Hard +35 mood, x33% sleep fall rate, +15% moving, x50% pain.

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