Opioid suppression of conditioned anticipatory brain responses to breathlessness

Abstract

Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7ng/ml target-controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness.

Keywords: Anticipation; Breathing; Breathlessness; Conditioning; FMRI; Opioid.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

Schematic illustration of experimental session and aversive conditioning paradigm. Prior to the application of each inspiratory load, the fixation cross on the screen changed to one of three shapes, a triangle, a square and a star to signal the imminent application of a stimulus (mild inspiratory load, strong inspiratory load) for eight seconds (anticipation period). The shape remained on the screen during the application of the stimulus (stimulus period) for 30–60 s and changed back to the fixation cross when the stimulus ceased. The shapes were counterbalanced across participants. Each inspiratory load was followed by an unloaded period of between 30 and 60 s that was indicated by a third visual cue. The use of relatively long breathlessness stimuli was chosen to maximize the emotional responses associated with anticipation of breathlessness. Participants rated their respiratory intensity and unpleasantness after each stimulus. Visual stimuli were generated and presented in white on a black background using the Cogent toolbox (www.vislab.ucl.ac.uk/Cogent/) for MatLab (MathWorks Inc., Natick, MA, USA).

Fig. 2

Breathlessness intensity and unpleasantness scores (on a visual-analogue scale of 0–100%) during unloaded breathing and breathlessness during both saline and remifentanil (Remi) administration. Bars represent group mean, and error bars standard deviation. *Significantly different between the groups (p<.05>

Fig. 3

BOLD activation contrasting anticipation of breathlessness with anticipation of no loading during saline administration. The image consists of a color-rendered statistical map superimposed on a standard (MNI) brain. Significant regions are displayed with a threshold of Z>2.3 with a cluster probability threshold of p

Fig. 4

BOLD activity corresponding with remifentanil-induced decreases in unpleasantness scores across subjects. Top: Increases in BOLD activity with remifentanil that negatively correlate with decreases in breathlessness unpleasantness, with a graphical depiction of the contrast of parameter estimate (COPE) from the significant activity in the rostral ACC plotted against the decrease in unpleasantness scores. Bottom: Decreases in BOLD activity with remifentanil that correlate with decreases in unpleasantness during anticipation of strong loading in the hippocampus and amygdala, with a graphical depiction of the contrast of parameter estimate (COPE) from the combined significant activity plotted against the decrease in unpleasantness scores. The image consists of a color-rendered statistical map superimposed on a standard (MNI) brain. The bright gray region delineates the region of interest analysed. Abbreviations: ACC, anterior cingulate cortex; NA, nucleus accumbens; paraCC, paracingulate cortex; prefrontal cortex; PC, precuneus; amyg, amygdala; ant hipp, anterior hippocampus.

Fig. 5

BOLD activity during the breathlessness condition during saline (placebo) infusion (top figure) and the effect of remifentanil infusion (lower figure). The image consists of a color-rendered statistical map superimposed on a standard (MNI) brain. Significant regions are displayed with a threshold of Z>2.3 and a cluster probability threshold of p