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  1. Evaluation Summary:

    This is a challenging study exploring the effects of a commonly used analgesic, remifentanil, on brain and spinal cord related pain processing in humans. It is of considerable interest to the pain research, neuroimaging and opioid neuroscience communities and are also relevant to clinicians who commonly use opioid infusions. The authors have used sophisticated methods for combined brain and spinal cord functional magnetic resonance imaging to examine the influence of an intravenous opioid on pain processing in the ascending and descending pain pathways in healthy subjects. The authors have conducted a comprehensive assessment in large numbers of subjects and have explored both changes in amplitude of activity as well as connectivity. Their detailed analysis strengthens findings from previous human and animal studies and extend to demonstrate novel changes in connectivity in the descending pathway to the spinal cord although these data are potentially compatible with alternative interpretations and may need to be reinforced by further analysis.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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  2. Joint Public Review:

    The authors have used their sophisticated and established methodology for combined cortico-spinal fMRI to examine the influence of remifentanil (a potent mu agonist) on pain processing in the ascending and descending pain pathways in healthy male subjects. They show an effect of the drug on pain report and also show a reduction of activity in a range of sites in the brain and midbrain that have previously been identified by meta-analysis as being linked to pain processing. They find that there is less deactivation in the sgACC with remi infusion. They show changes in spinal bold during the infusion that they link to the analgesic effect. Connectivity analyses show that coupling between the vmPFC and PAG and spinal cord is differentially modulated in subjects having remifentanil compared to normal saline. They conclude that these alterations of coupling in the descending pain system may be involved in the mediation of the analgesic effects of opioids which provides additional human evidence to support prior animal experiments demonstrating such effects. While some of these results are already known - in terms of how remifentanil produces changes in pain related brain activity at a group and individual level and as this activity relates to behavioural analgesia - the additional contributions with the spinal cord data are welcome. Further, the ability to explore connectivity changes between the brain and spinal cord during pharmacological analgesia is a real plus. It is a shame the expectation manipulation did not work. In general the authors should be congratulated for performing an impressive study.

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