PainRelief.com: What are the main findings?

Response: It has been long thought that placebo is mediated by a part of the brainstem called the ventrolateral periaqueductal gray region. This stems mainly from the finding that placebo is mediated by opiates and that vlPAG stimulation evokes an opiate-mediated analgesia. However, we recently used ultra-high field fMRI to show that is actually the adjacent lateral PAG that is activated during placebo. This region mediates a non-opiate analgesia upon stimulation. We also recently showed that the rostral lPAG is activated by face pain whereas the caudal lPAG is activated by body pain – a crude somatotopic map. Given this we hypothesised that face analgesia would involve the rostral lPAG and body analgesia the caudal lPAG – and this is what we found.

PainRelief.com: How is this brainstem circuitry affected by opioids and other analgesics?

Response: The circuitry we describe as showing somatotopic properties – the PAG-RVM axis – we know can be directly modulated by both pharmacological and direct electrical stimulation interventions. Some of the seminal work which first established this circuitry was performed in experimental animals in the 1980’s, where it was shown that stimulating the PAG caused produces pain relief, and this work was later also reproduced in humans.

In terms of how analgesics or pharmacological interventions alter the circuit, I think more interesting than analgesics is the action of opioid and cannabinoid antagonists (blockers), which can change the production of placebo analgesia in humans. We know that Naloxone when given alongside placebo morphine can reduce / completely abolish placebo analgesia responses – and it was thought, until our recent work, that is likely mediated through the vlPAG-RVM axis. However we recently showed that it is in fact the lPAG that is activated during placebo analgesia and the lPAG when stimulated evokes a non-opiate mediated analgesia. Given this, it is likely that the effects of opiate antagonists on placebo are acting at higher brain regions, potentially in the cingulate or prefrontal cortices.

PainRelief.com: What should readers take away from your report?

Response: I think the main take away is that the brainstem contains a circuit that can produce a powerful analgesia in a specific part of the body.

PainRelief.com: What recommendations do you have for future research as a result of this study?

Response: Given we suggest there are distinct areas of the PAG that are activated to produce site specific analgesic effect, the ability to target this precise location to see if this alleviates any clinical pain condition with a pain spread that predominantly occupies a certain area – such as Sciatica or Migraine – for the lower and orofacial areas respectively for instance – would be a really interested line of research.

PainRelief.com: Is there anything else you would like to add?

Response:  My only addition would be that this manuscript particularly has taught me that research takes a whole team to be done right. Beyond my co-authors, there was an enormous amount of time and effort devoted by the scanning team based in Melbourne that assisted with ensuring we could book time appropriately after initial submission to return reviewer queries and requests for additional experiments in a timely manner, as well as the accommodations afforded by the University of Sydney, at both the faculty level in Medicine and Health, and my research centre level at the Brain and Mind centre – where I have had the pleasure of extensive mentorship, feedback, and ideas generation on subjects relating and extending from this research.

I am extremely grateful to the connections I’ve made and the mentors that have shaped this work and it would not have been possible without this whole end-to-end team backing me up.

Citation: Lewis S. Crawford et al.

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Somatotopic organization of brainstem analgesic circuitry.Science 389,eadu8846(2025).DOI:10.1126/science.adu8846

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Last Updated on September 3, 2025 by PainRelief.com