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A study has revealed that the human brainstem contains distinct regions for managing pain depending on where it occurs in the body. Researchers from the University of Sydney identified this spatial organization by inducing placebo pain relief and tracking brain activity using high-resolution neuroimaging.
The results, published in Science, may provide a framework for developing more targeted, non-opioid treatments for chronic pain.
“This is the first time we’ve seen such a precise and detailed pain map in the human brainstem, showing us that it tailors pain relief to the specific part of the body that’s experiencing it.”
Dr. Lewis Crawford.
Placebo effects reveal spatially-organised pain control
Researchers enrolled 93 healthy volunteers and used heat stimuli to simulate pain in different body areas. A placebo cream was applied, and the temperature of the stimulus was quietly reduced, training participants to associate the cream with pain relief.
Later, participants received the same level of pain stimulation on both the placebo-treated area and an untreated control area. A majority of individuals continued to report lower pain in the area previously exposed to the placebo cream, indicating a maintained placebo response.
During these tests, researchers used 7-Tesla functional magnetic resonance imaging (fMRI), a form of high-resolution brain scanning, to observe brainstem activity. They found that two key areas – the periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM) – were involved in mediating pain relief. Importantly, different subregions were active depending on whether the pain was located on the face, arm or leg.
Periaqueductal grey (PAG)
The periaqueductal grey is a region of grey matter located around the cerebral aqueduct in the brainstem. It is involved in modulating pain and coordinating defensive behaviors.
Rostral ventromedial medulla (RVM)
The rostral ventromedial medulla is a part of the medulla oblongata in the brainstem. It works with the PAG to regulate the transmission of pain signals to the spinal cord, making it a critical structure in pain modulation.
7-Tesla fMRI
7-Tesla functional magnetic resonance imaging is a high-resolution imaging technology that uses a magnetic field strength of 7 Tesla.
Activity in the upper sections of these structures was associated with facial pain relief, while lower regions were engaged when pain was induced in the limbs.
The brain’s pain relief is anatomically specific
The study challenges the idea that the brain’s pain regulation system functions as a single, uniform mechanism. Instead, it suggests that pain control is anatomically mapped, with localized brainstem activity tuned to the part of the body experiencing pain.
“The brain’s natural pain relief system is more nuanced than we thought. Essentially, it has a built-in system to control pain in specific areas. It’s not just turning pain off everywhere; but working in a highly coordinated, anatomically precise system.”
Dr. Lewis Crawford.
This organization may explain why placebo effects are limited to areas where the brain expects relief. The spatial patterning observed in the PAG and RVM supports a model of targeted neuromodulation rather than global suppression.
Implications for future pain therapies
The researchers suggest that this newly identified brainstem map could guide the development of therapies that activate specific circuits without producing systemic effects. Such treatments may be particularly beneficial for individuals with localized chronic pain.
The findings also raise questions about the neurochemical basis of placebo analgesia. Contrary to previous assumptions that placebo effects operate through the brain’s opioid system, this study points to the lateral PAG – a region thought to be more closely associated with cannabinoid signaling – as a key site of non-opioid placebo analgesia.
Placebo analgesia
Placebo analgesia refers to the reduction of pain following the administration of a substance or procedure with no therapeutic effect.
By identifying where and how pain relief occurs in the brain, the research highlights a possible role for cannabinoid-based pathways in targeted pain control.
Reference: Crawford LS, Tinoco Mendoza FA, Robertson RV, et al. Somatotopic organization of brainstem analgesic circuitry. Science. 2025;389(6763):eadu8846. doi: 10.1126/science.adu8846
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