Simultaneous brain, brainstem and spinal cord pharmacological-fMRI reveals involvement of an endogenous opioid network in attentional analgesia

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Abstract

Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) - rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans we used simultaneous whole brain-spinal cord pharmacological-fMRI (N=39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.

Data availability

ource data is provided for Figure 2 (A, C, D, E, and supplementary 1, 2 and 3) and Figure 4 (B) and Figure 5. Un-thresholded statistical maps have been shared in Open Science Framework and are available at the following link: https://osf.io/dtpr6/ and the brainstem regional masks of PAG, LC, RVM are available from https://osf.io/xqvb6/

Article and author information

Author details

Valeria Oliva

Department of Anesthesiology, University of California, San Diego, La Jolla, United States

Competing interests
No competing interests declared.
Ron Hartley-Davies

School of Psychological Science, University of Bristol, Bristol, United Kingdom

Competing interests
No competing interests declared.
Rosalyn Moran

Department of Neuroimaging, King's College London, London, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-0227-6548
Anthony E Pickering

School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom

For correspondence
tony.pickering@bristol.ac.uk

Competing interests
Anthony E Pickering, declares that he has unrelated research funding for a collaboration with Eli Lilly and is onthe advisory board for Lateral Pharma for an unrelated study..

"This ORCID iD identifies the author of this article:" 0000-0003-0345-0456
Jonathan CW Brooks

School of Psychological Science, University of Bristol, Bristol, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-3335-6209

Funding

Wellcome Trust (203963/Z/16/Z)

Valeria Oliva

Wellcome Trust (088373/Z/09/A)

Anthony E Pickering

Medical Research Council

Jonathan CW Brooks

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study was approved by the University of Bristol Faculty of Science Human Research Ethics Committee (reference 23111759828). All participants were given a participant information sheet. In the first screening/calibration visit, the participants were briefed on the experiment and gave written informed consent.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.