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The Journal of Neuroscience, June 24, 2009, 29(25):8177-8186; doi:10.1523/JNEUROSCI.1375-09.2009

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Behavioral/Systems/Cognitive
Opioids Depress Cortical Centers Responsible for the Volitional Control of Respiration

Kyle T. S. Pattinson,^1,2 Ricardo J. Governo,^2,3 Bradley J. MacIntosh,² Elizabeth C. Russell,^1,2 Douglas R. Corfield,⁴ Irene Tracey,^1,2 and Richard G. Wise^2,5

¹Nuffield Department of Anaesthetics and ²Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom, ³Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex BN1 9PX, United Kingdom, ⁴Institute for Science and Technology in Medicine, Keele University, Staffordshire ST5 5BG, United Kingdom, and ⁵Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff CF10 3AT, United Kingdom

Correspondence should be addressed to Kyle T. S. Pattinson, Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. Email: kyle.pattinson{at}nda.ox.ac.uk

Respiratory depression limits provision of safe opioid analgesia and is the main cause of death in drug addicts. Although opioids are known to inhibit brainstem respiratory activity, their effects on cortical areas that mediate respiration are less well understood. Here, functional magnetic resonance imaging was used to examine how brainstem and cortical activity related to a short breath hold is modulated by the opioid remifentanil. We hypothesized that remifentanil would differentially depress brain areas that mediate sensory-affective components of respiration over those that mediate volitional motor control. Quantitative measures of cerebral blood flow were used to control for hypercapnia-induced changes in blood oxygen level-dependent (BOLD) signal. Awareness of respiration, reflected by an urge-to-breathe score, was profoundly reduced with remifentanil. Urge to breathe was associated with activity in the bilateral insula, frontal operculum, and secondary somatosensory cortex. Localized remifentanil-induced decreases in breath hold-related activity were observed in the left anterior insula and operculum. We also observed remifentanil-induced decreases in the BOLD response to breath holding in the left dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, and periaqueductal gray, brain areas that mediate task performance. Activity in areas mediating motor control (putamen, motor cortex) and sensory-motor integration (supramarginal gyrus) were unaffected by remifentanil. Breath hold-related activity was observed in the medulla. These findings highlight the importance of higher cortical centers in providing contextual awareness of respiration that leads to appropriate modulation of respiratory control. Opioids have profound effects on the cortical centers that control breathing, which potentiates their actions in the brainstem.

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Received March 23, 2009; accepted May 16, 2009.

Correspondence should be addressed to Kyle T. S. Pattinson, Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. Email: kyle.pattinson{at}nda.ox.ac.uk

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