We’ve recently published a paper on how opioids can modulate breathlessness. (The whole manuscript is open access here). Low-dose opioids can be used for treating chronic breathlessness, but we don’t know exactly how they work.
Opioid receptors exist across the brain. These are part of the internal opioid system (endogenous opioid system) for natural pain relief. When opioids are used in the clinical setting to treat negative stimuli, such as pain, they influence the unpleasantness and the intensity of the stimulus in different ways(1). In terms of breathing, opioids lower breathing by influencing brainstem respiratory centres(2), causing breathing to stop completely in high doses, and they can also affect higher brain centres(3).
Opioids also have behavioural effects, and may, amongst other things, influence associative learning. Associative learning is when an association between two stimuli is learnt by pairing these together. For example, in chronic breathlessness this could be previously neutral stimuli (e.g. a flight of stairs) and breathlessness. This could create an anticipatory threat response, which means that simply seeing a flight of stairs is enough to bring about breathlessness or the fear associated with breathlessness. This can worsen the breathlessness for the patient in the long run.
In this study, we hypothesized that opioids improve breathlessness in part through changing the anticipatory response to breathlessness. We focused on two brain regions in particular: the amygdala and hippocampus. Both are strongly involved in associative learning(4) and are rich in opioid receptors(5,6).
What did we do? First, we asked healthy volunteers to do a breathing test where we paired three different degrees of breathlessness and three symbols. The symbols were presented immediately before the volunteer was made breathless and were matched to the level of breathlessness that they signified. We invited those volunteers who learnt to associate each different symbol and its corresponding breathlessness to undertake two MRI scans in random order. Before one scan they received a low-level opioid (remifentanil) infusion, and before the other they received a control (saline) infusion. During the scans, the volunteers repeated the breathlessness/symbol task. Below is a schematic of the breathing circuit used for the study, showing how different levels of breathlessness was induced.
Figure 1. Breathing circuit for inducing breathlessness
What did we find? We were able to show that breathlessness anticipation in the control condition was processed in the right anterior insula and operculum, and that the breathlessness itself was processed in the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex, primary sensory cortices and motor cortices. These regions have been identified in other studies on breathlessness (as discussed in a previous blogpost).
However, in the opioid condition, we saw the following:
1. Opioids reduced breathlessness unpleasantness (Figure 2)
2. This reduction correlated with reduced activity in the amygdala and hippocampus during anticipation of breathlessness (Figure 3)
3. This reduction also correlated with increased activity in the anterior cingulate cortex and nucleus accumbens during the actual breathlessness (Figure 3)
4. During the actual breathlessness, the opioid infusion directly reduced activity in the anterior insula, anterior cingulate cortex and sensory motor cortices (Figure 4).
Figure 2. Ratings of breathlessness and intensity. Abbreviation: Remi=remifentanil
Reduction in unpleasantness. The reduction in unpleasantness with opioids was expected – the different effect of opioids on intensity and unpleasantness has been shown in many other negative conditions, including pain(1). Interestingly, we could confirm that this lowered unpleasantness correlated with reduced activity in brain regions linked with associative learning and memory (amygdala and hippocampus) before the breathlessness began (Figure 3, bottom). This reduced activation in the amygdala and hippocampus, regions that are needed for formation of unpleasant memories, may explain how low-dose opioids gradually become more efficient as a therapy over the first week of administration. The reduction in amygdala/hippocampus activation may mean that fewer new negative memories and reaction patterns are formed.
Figure 3. Brain activity linked to lowered unpleasantness, relating to breathlessness (top) and anticipation of breathlessness (bottom). NA=nucleus accumbens, paraCC=paracingulate cortex, ACC=anterior cingulate cortex, PC=precuneus, ant hipp=anterior hippocampus, amyg=amygdala.
We also see that the reduced unpleasantness correlates with activation during the actual breathlessness in the anterior cingulate cortex and nucleus accumbens (Figure 3, top). These are parts of the endogenous opioid system which reduces the perception of negative stimuli. This means that the reduced unpleasantness our volunteers felt is linked with these regions being more active. In other words, they may act to further dampen the negative sensation. Less unpleasantness during the breathlessness means that even less negative memories are likely to be formed.
Reduction in breathlessness activation. Finally, opioids directly reduced activity in the anterior insula, anterior cingulate cortex, sensory motor cortices and brainstem (Figure 4). The activation during control (saline) in the figure below is typical of breathlessness, and has been found in several other studies using breathing challenges.
Figure 4. Brain activity during breathlessness in the control (saline) condition (top) and where it is reduced by the opioid (remifentanil, bottom). Increased activation is shown in red-yellow, and decreased in blue. M1/S1=primary motor & sensory cortices, OP=operculum, dlPFC=dorsolateral prefrontal cortex, Thal=thalamus, ACC=anterior cingulate cortex, vmPFC=ventromedial prefrontal cortex, PAG=periaqueductal grey, SMG=supramarginal gyrus.
The areas that are reduced in activation with opioids are commonly activated in breathlessness and central to respiratory sensation. For example, the anterior insula, the most commonly activated brain region during breathlessness, is believed to assess the quality of the stimulus and help control interpretation. The anterior cingulate cortex, which is also commonly activated in breathlessness, is similarly involved in control of negative emotions. These regions may be part of an interpretation process that is shaped by expectation and learning(7) similar to other control systems in the body (e.g.(8)).
Summary: Opioids manipulate brain regions associated with learning, negative memory formation and negative stimulus control. We have shown that the opioid remifentanil may alter breathlessness perception and the brain regions associated both with anticipation of and actual breathlessness. This suggests that opioids work to reduce breathlessness in part through direct effects on respiratory control mechanisms in the brainstem, insula and anterior cingulate cortex, and in part through changes in how breathlessness is anticipated, by changing associative learning processes in the amygdala/hippocampus.
1. Pain, 22 (1985), pp. 261–269
2. Br J Anaesth, 100 (2008), pp. 747–758
3. J Neurosci, 29 (2009), pp. 8177–8186
4. Curr Opin Neurobiol, 14 (2004), pp. 198–202
5. Life Sci, 83 (2008), pp. 644–650
6. Pain, 96 (2002), pp. 153–162
7. Nat Rev Neurosci, 16 (2015), pp. 419-429
8. Exp Physiol, 92 (2007), pp. 695-704
All images presented with permission, creative commons licence.