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. 2022 Dec 1;43(17):5235-5249.
doi: 10.1002/hbm.25999. Epub 2022 Jul 7.

Neurotransmitter receptor densities are associated with changes in regional Cerebral blood flow during clinical ongoing pain

Alexandros Vamvakas  1   2 , Timothy Lawn  2 , Mattia Veronese  2 , Steven C R Williams  2 , Ioannis Tsougos  1   2 , Matthew A Howard  2
Affiliations

Neurotransmitter receptor densities are associated with changes in regional Cerebral blood flow during clinical ongoing pain

Alexandros Vamvakas et al. Hum Brain Mapp. .

Abstract

Arterial spin labelling (ASL) plays an increasingly important role in neuroimaging pain research but does not provide molecular insights regarding how regional cerebral blood flow (rCBF) relates to underlying neurotransmission. Here, we integrate ASL with positron emission tomography (PET) and brain transcriptome data to investigate the molecular substrates of rCBF underlying clinically relevant pain states. Two data sets, representing acute and chronic ongoing pain respectively, were utilised to quantify changes in rCBF; one examining pre-surgical versus post-surgical pain, and the second comparing patients with painful hand Osteoarthritis to a group of matched controls. We implemented a whole-brain spatial correlation analysis to explore associations between change in rCBF (ΔCBF) and neurotransmitter receptor distributions derived from normative PET templates. Additionally, we utilised transcriptomic data from the Allen Brain Atlas to inform distributions of receptor expression. Both datasets presented significant correlations of ΔCBF with the μ-opioid and dopamine-D2 receptor expressions, which play fundamental roles in brain activity associated with pain experiences. ΔCBF also correlated with the gene expression distributions of several receptors involved in pain processing. Overall, this is the first study illustrating the molecular basis of ongoing pain ASL indices and emphasises the potential of rCBF as a biomarker in pain research.

Keywords: Allen brain atlas; arterial spin labelling; neurotransmitter receptors; osteoarthritis; pain; positron emission tomography.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Statistical framework for ΔCBF calculation and correlation with PET templates. PET, positron emission tomography
FIGURE 2
FIGURE 2
Bar plots showing the mean ± SD pain intensity ratings of all subjects pCASL scans within each session, as indexed by VAS for TME participants (left chart) and NRS for OA patients (right chart). NRS, numerical rating scale; OA, osteoarthritis; TME, third molar extraction; VAS, visual analogue scale
FIGURE 3
FIGURE 3
TME study regression plots: Scatterplots of the 85 VOIs (dots) displaying the relationship of the average regional CBF change (ΔCBF) between pain and non‐pain states of TME dataset with average regional BPnd values of the six receptor templates utilised. The linear regression curve (red line) and 95% confidence bounds (dashed lines) are shown. The dots are presented color‐coded as shown in the figure legend to provide a coarse positioning of the VOIs into the brain. BPnd, binding potential; CBF, cerebral blood flow; TME, third molar extraction; VOI, volumes of interest
FIGURE 4
FIGURE 4
OA regression plots: Scatterplots of the 85 VOIs (dots) displaying the relationship of the average regional CBF change (ΔCBF) between pain and nonpain states of OA and controls datasets with average regional BPnd values of the six receptor templates utilised. The linear regression curve (red line) and 95% confidence bounds (dashed lines) are shown. The dots are presented color‐coded as shown in the figure legend to provide a coarse positioning of the VOIs into the brain. BPnd, binding potential; CBF, cerebral blood flow; OA, osteoarthritis; VOI, volumes of interest
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