Researchers from the University of Sydney have used placebo pain relief to uncover a map-like system in the brainstem that controls pain differently depending on where it’s felt in the body. The findings may pave the way for safer, more targeted treatments for chronic pain that don’t rely on opioids.
Like a highway, the brainstem connects the brain to the spinal cord and manages all signals going to and from the brain. It produces and releases nearly all the neurochemicals needed for thinking, survival and sensing.
Published in Science, the study used 7-Tesla functional magnetic resonance imaging (fMRI) – one of the most powerful brain scanners available, with only two in Australia – to pinpoint how two key brainstem regions manage pain through placebo effects.
Dr Lewis Crawford, lead author and research fellow at the School of Medical Sciences and the Brain and Mind Centre, said: “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.”
The study builds on decades of work by one of the authors, Professor Kevin Keay, Deputy Head of the School of Medical Sciences and a mentor to Dr Crawford.
How placebo pain relief works
Researchers exposed 93 healthy participants to heat pain on different body parts and applied a placebo pain relief cream while secretly lowering the temperature, conditioning them to believe the cream was alleviating their pain.
The temperature used was individually adjusted to be moderately painful as perceived by each participant. Researchers used a self-report scale, where 0 was no pain and 100 was the worst pain imaginable, and sought a temperature between 40-50 for each participant.
Later, the same pain stimulus was applied to the placebo-treated area as well as a separate untreated area for comparison. Up to 61 percent of participants still reported less pain in the area where the placebo cream was originally applied, typical of a true placebo response.
“We found that upper parts of the brainstem were more active when relieving facial pain, while lower regions were engaged for arm or leg pain,” said Dr Crawford.
Two key brainstem regions are involved in this process: the periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM). These areas showed distinct patterns of activity depending on where pain relief was directed, with the upper parts of the PAG and RVM more active for facial pain, while lower parts were more active for arm or leg pain.
“The brain’s natural pain relief system is more nuanced than we thought,” said Dr Crawford. “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.”
This could lead to more precise treatments for chronic pain that don’t rely on opioids and work exactly where the brain expects pain relief to occur.
Dr Lewis Crawford
School of Medical Sciences
A new way to target pain relief
Understanding which brainstem areas are linked to different parts of the body may open new avenues for developing non-invasive therapies that reduce pain without widespread side effects.
“We now have a blueprint for how the brain controls pain in a spatially organised way,” said Professor Luke Henderson, senior author and Professor in the School of Medical Sciences and the Brain and Mind Centre. “This could help us design more effective and personalised treatments, especially for people with chronic pain in a specific area of their body.”
The study also challenges long-held assumptions about how placebo pain relief works. Instead of relying on the brain’s opioid system, experts say a different part of the brainstem – the lateral PAG – is not only responsible but works without using opioids and could instead be linked to cannabinoid activity.
“Opioid-based pain relief typically activates central areas of the brain and can affect the whole body, whereas the cannabinoid circuit that we identified appears to operate in more targeted regions of the brainstem,” said Dr Crawford. “This supports the idea that cannabinoids may play a role in localised, non-opioid pain control.
“Knowing exactly where pain relief is happening in the brain means we can target that area or assess whether a drug is working in the right place,” said Dr Crawford. “This could lead to more precise treatments for chronic pain that don’t rely on opioids and work exactly where the brain expects pain relief to occur – a huge step forward for pain management.”
Research
Crawford, Lewis S, Henderson, Luke A, et al., Somatotopic organisation of brainstem analgesic circuitry (Science, 2025)
DOI: 10.1126/science.adu8846
Declaration
The research was approved by the University of Sydney Human Research Ethics Committee (2019/037) and all participants gave written informed consent. The authors declare no competing interests.
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