Cortico-spinal coupling along descending pain system differentiates between opioid and saline treatment in healthy participants

  1. Alexandra Tinnermann
  2. Christian Sprenger
  3. Christian Büchel

  • Curated by eLife

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    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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Abstract

Opioids are potent analgesic drugs with widespread cortical, subcortical and spinal targets. In particular, the central pain system comprising ascending and descending pain pathways has high opioid receptor densities and is thus crucial for opioid analgesia. Here, we investigated effects of the opioid remifentanil in a large sample (n=78) of healthy male participants using combined cortico-spinal fMRI. This approach offers the possibility to measure BOLD responses simultaneously in the brain and spinal cord allowing us to investigate the role of cortico-spinal coupling in opioid analgesia. Our data show that opioids altered activity in regions involved in pain processing such as somatosensory regions including the spinal cord and pain modulation such as prefrontal regions. Moreover, coupling strength along the descending pain system, i.e. between the medial prefrontal cortex, periaqueductal gray and spinal cord was stronger in participants who reported stronger analgesia during opioid treatment while the reversed pattern was observed in the control group. These results indicate that coupling along the descending pain pathway is a potential mechanism of opioid analgesia and can differentiate between opioid analgesia and unspecific reductions in pain such as habituation.

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  1. eLife

    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.)

  2. eLife

    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.

  3. Version 2 published on bioRxiv
  4. Version 1 published on bioRxiv