TY - JOUR T1 - Altered signaling in the descending pain modulatory system after short-term infusion of the μ-opioid agonist remifentanil JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.2496-17.2018 SP - 2496-17 AU - Christian Sprenger AU - Iris-Carola Eichler AU - Lars Eichler AU - Christian Zöllner AU - Christian Büchel Y1 - 2018/02/12 UR - http://www.jneurosci.org/content/early/2018/02/12/JNEUROSCI.2496-17.2018.abstract N2 - μ-Opioid receptor agonists are widely used within the contemporary treatment of pain but abrupt opioid suspension, even after short-term infusion, can paradoxically increase the sensitivity to noxious stimuli - a phenomenon that has been for example reported after application of the fast-acting μ-opioid receptor agonist remifentanil. To investigate the mechanisms underlying the effects of discontinuation of remifentanil application on pain processing in the human CNS, we analyzed neuronal responses to thermal stimuli before and after a short-term infusion of remifentanil (30 min 0.1 μg/kg-bodyweight/min) compared to control in the brain, brainstem and spinal cord in drug-naïve male volunteers employing functional magnetic resonance imaging. Subsequent to remifentanil suspension we observed reduced heat pain thresholds and increased neuronal responses in pain encoding as well as in key regions of the descending pain modulatory system, such as the periaqueductal grey matter, the nucleus cuneiformis and the rostral ventromedial medulla. Moreover, the spinal pain-related multi-voxel activity pattern showed an opioid-specific change after drug suspension. Importantly, remifentanil suspension increased the functional coupling between the nucleus cuneiformis and the rostral anterior cingulate cortex, and the coupling strength between the rostral anterior cingulate cortex and the nucleus cuneiformis correlated negatively with the individual pain threshold after opioid suspension. These findings demonstrate that already subsequent to a short-term infusion of the μ-opioid receptor agonist remifentanil signaling in the descending pain modulatory system is fundamentally altered and that these changes are directly related to the behavioral sensitivity to pain.Significance Statement:Opioids are widely used in modern medicine but besides their known side effects it is increasingly recognized that opioids can also increase sensitivity to pain subsequent to their use. Employing the fast-acting μ-opioid receptor agonist remifentanil and fMRI in healthy male volunteers this study demonstrates how signaling changes occur along the entire descending pain modulatory pathway after opioid discontinuation and how these alterations are closely linked to increased behavioral pain sensitivity. Particularly, by revealing modified responses in pain modulatory brainstem regions that have been previously demonstrated to be causally involved in acute opioid withdrawal effects in rodents the data provide a plausible neuronal mechanism by which the increased sensitivity to pain after opioid suspension is mediated in humans. ER -