Opioid suppression of conditioned anticipatory brain responses to breathlessness
Anja Hayen, Vishvarani Wanigasekera, Olivia K Faull, Stewart F Campbell, Payashi S Garry, Simon J M Raby, Josephine Robertson, Ruth Webster, Richard G Wise, Mari Herigstad, Kyle T S Pattinson, Anja Hayen, Vishvarani Wanigasekera, Olivia K Faull, Stewart F Campbell, Payashi S Garry, Simon J M Raby, Josephine Robertson, Ruth Webster, Richard G Wise, Mari Herigstad, Kyle T S Pattinson
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](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5391989/bin/gr1.jpg)
![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5391989/bin/gr2.jpg)
Fig. 3
BOLD activation contrasting anticipation of…
Fig. 3
BOLD activation contrasting anticipation of breathlessness with anticipation of no loading during saline…
Fig. 4
BOLD activity corresponding with remifentanil-induced…
Fig. 4
BOLD activity corresponding with remifentanil-induced decreases in unpleasantness scores across subjects. Top: Increases…
Fig. 5
BOLD activity during the breathlessness…
Fig. 5
BOLD activity during the breathlessness condition during saline (placebo) infusion (top figure) and…
- Opioids depress cortical centers responsible for the volitional control of respiration.Pattinson KT, Governo RJ, MacIntosh BJ, Russell EC, Corfield DR, Tracey I, Wise RG. Pattinson KT, et al. J Neurosci. 2009 Jun 24;29(25):8177-86. doi: 10.1523/JNEUROSCI.1375-09.2009. J Neurosci. 2009. PMID: 19553457 Free PMC article.
- Altered Signaling in the Descending Pain-modulatory System after Short-Term Infusion of the μ-Opioid Agonist Remifentanil.Sprenger C, Eichler IC, Eichler L, Zöllner C, Büchel C. Sprenger C, et al. J Neurosci. 2018 Mar 7;38(10):2454-2470. doi: 10.1523/JNEUROSCI.2496-17.2018. Epub 2018 Feb 12. J Neurosci. 2018. PMID: 29440535 Free PMC article.
- Fear conditioning in an abdominal pain model: neural responses during associative learning and extinction in healthy subjects.Kattoor J, Gizewski ER, Kotsis V, Benson S, Gramsch C, Theysohn N, Maderwald S, Forsting M, Schedlowski M, Elsenbruch S. Kattoor J, et al. PLoS One. 2013;8(2):e51149. doi: 10.1371/journal.pone.0051149. Epub 2013 Feb 26. PLoS One. 2013. PMID: 23468832 Free PMC article.
- Breathlessness amplifies amygdala responses during affective processing.Stoeckel MC, Esser RW, Gamer M, von Leupoldt A. Stoeckel MC, et al. Psychophysiology. 2018 Sep;55(9):e13092. doi: 10.1111/psyp.13092. Epub 2018 Apr 17. Psychophysiology. 2018. PMID: 29667212
- Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness.Barnes H, McDonald J, Smallwood N, Manser R. Barnes H, et al. Cochrane Database Syst Rev. 2016 Mar 31;3(3):CD011008. doi: 10.1002/14651858.CD011008.pub2. Cochrane Database Syst Rev. 2016. PMID: 27030166 Free PMC article. Review.
- Interoception of breathing and its relationship with anxiety.Harrison OK, Köchli L, Marino S, Luechinger R, Hennel F, Brand K, Hess AJ, Frässle S, Iglesias S, Vinckier F, Petzschner FH, Harrison SJ, Stephan KE. Harrison OK, et al. Neuron. 2021 Dec 15;109(24):4080-4093.e8. doi: 10.1016/j.neuron.2021.09.045. Epub 2021 Oct 20. Neuron. 2021. PMID: 34672986 Free PMC article.
- Investigating the specificity of the neurologic pain signature against breathlessness and finger opposition.Harrison OK, Hayen A, Wager TD, Pattinson KTS. Harrison OK, et al. Pain. 2021 Dec 1;162(12):2933-2944. doi: 10.1097/j.pain.0000000000002327. Pain. 2021. PMID: 33990110 Free PMC article.
- Breathlessness in COPD: linking symptom clusters with brain activity.Finnegan SL, Harrison OK, Harmer CJ, Herigstad M, Rahman NM, Reinecke A, Pattinson KTS. Finnegan SL, et al. Eur Respir J. 2021 Nov 18;58(5):2004099. doi: 10.1183/13993003.04099-2020. Print 2021 Nov. Eur Respir J. 2021. PMID: 33875493 Free PMC article.
- Multi-Level Regulation of Opioid-Induced Respiratory Depression.Palkovic B, Marchenko V, Zuperku EJ, Stuth EAE, Stucke AG. Palkovic B, et al. Physiology (Bethesda). 2020 Nov 1;35(6):391-404. doi: 10.1152/physiol.00015.2020. Physiology (Bethesda). 2020. PMID: 33052772 Free PMC article. Review.
- Remote, Automated, and MRI-Compatible Administration of Interoceptive Inspiratory Resistive Loading.Rieger SW, Stephan KE, Harrison OK. Rieger SW, et al. Front Hum Neurosci. 2020 May 12;14:161. doi: 10.3389/fnhum.2020.00161. eCollection 2020. Front Hum Neurosci. 2020. PMID: 32477083 Free PMC article.
-
- Bingel U., Wanigasekera V., Wiech K., Ni Mhuircheartaigh R., Lee M.C., Ploner M., Tracey I. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci. Transl. Med. 2011;3:70ra14. - PubMed
-
- Bond A., Lader M. Use of analog scales in rating subjective feelings. Br. J. Med. Psychol. 1974;47:211–218.
-
- Brooks J.C., Beckmann C.F., Miller K.L., Wise R.G., Porro C.A., Tracey I., Jenkinson M. Physiological noise modelling for spinal functional magnetic resonance imaging studies. Neuroimage. 2008;39:680–692. - PubMed
- Randomized Controlled Trial
- Adult
- Analgesics, Opioid / pharmacology*
- Brain / drug effects*
- Conditioning, Classical / drug effects*
- Double-Blind Method
- Dyspnea / psychology*
- Female
- Functional Neuroimaging
- Humans
- Magnetic Resonance Imaging
- Male
- Piperidines / pharmacology*
- Remifentanil
- Analgesics, Opioid
- Piperidines
- Remifentanil
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
NCBI Literature Resources
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![Fig. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5391989/bin/gr3.jpg)
Fig. 4
BOLD activity corresponding with remifentanil-induced…
Fig. 4
BOLD activity corresponding with remifentanil-induced decreases in unpleasantness scores across subjects. Top: Increases…
Fig. 5
BOLD activity during the breathlessness…
Fig. 5
BOLD activity during the breathlessness condition during saline (placebo) infusion (top figure) and…
- Opioids depress cortical centers responsible for the volitional control of respiration.Pattinson KT, Governo RJ, MacIntosh BJ, Russell EC, Corfield DR, Tracey I, Wise RG. Pattinson KT, et al. J Neurosci. 2009 Jun 24;29(25):8177-86. doi: 10.1523/JNEUROSCI.1375-09.2009. J Neurosci. 2009. PMID: 19553457 Free PMC article.
- Altered Signaling in the Descending Pain-modulatory System after Short-Term Infusion of the μ-Opioid Agonist Remifentanil.Sprenger C, Eichler IC, Eichler L, Zöllner C, Büchel C. Sprenger C, et al. J Neurosci. 2018 Mar 7;38(10):2454-2470. doi: 10.1523/JNEUROSCI.2496-17.2018. Epub 2018 Feb 12. J Neurosci. 2018. PMID: 29440535 Free PMC article.
- Fear conditioning in an abdominal pain model: neural responses during associative learning and extinction in healthy subjects.Kattoor J, Gizewski ER, Kotsis V, Benson S, Gramsch C, Theysohn N, Maderwald S, Forsting M, Schedlowski M, Elsenbruch S. Kattoor J, et al. PLoS One. 2013;8(2):e51149. doi: 10.1371/journal.pone.0051149. Epub 2013 Feb 26. PLoS One. 2013. PMID: 23468832 Free PMC article.
- Breathlessness amplifies amygdala responses during affective processing.Stoeckel MC, Esser RW, Gamer M, von Leupoldt A. Stoeckel MC, et al. Psychophysiology. 2018 Sep;55(9):e13092. doi: 10.1111/psyp.13092. Epub 2018 Apr 17. Psychophysiology. 2018. PMID: 29667212
- Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness.Barnes H, McDonald J, Smallwood N, Manser R. Barnes H, et al. Cochrane Database Syst Rev. 2016 Mar 31;3(3):CD011008. doi: 10.1002/14651858.CD011008.pub2. Cochrane Database Syst Rev. 2016. PMID: 27030166 Free PMC article. Review.
- Interoception of breathing and its relationship with anxiety.Harrison OK, Köchli L, Marino S, Luechinger R, Hennel F, Brand K, Hess AJ, Frässle S, Iglesias S, Vinckier F, Petzschner FH, Harrison SJ, Stephan KE. Harrison OK, et al. Neuron. 2021 Dec 15;109(24):4080-4093.e8. doi: 10.1016/j.neuron.2021.09.045. Epub 2021 Oct 20. Neuron. 2021. PMID: 34672986 Free PMC article.
- Investigating the specificity of the neurologic pain signature against breathlessness and finger opposition.Harrison OK, Hayen A, Wager TD, Pattinson KTS. Harrison OK, et al. Pain. 2021 Dec 1;162(12):2933-2944. doi: 10.1097/j.pain.0000000000002327. Pain. 2021. PMID: 33990110 Free PMC article.
- Breathlessness in COPD: linking symptom clusters with brain activity.Finnegan SL, Harrison OK, Harmer CJ, Herigstad M, Rahman NM, Reinecke A, Pattinson KTS. Finnegan SL, et al. Eur Respir J. 2021 Nov 18;58(5):2004099. doi: 10.1183/13993003.04099-2020. Print 2021 Nov. Eur Respir J. 2021. PMID: 33875493 Free PMC article.
- Multi-Level Regulation of Opioid-Induced Respiratory Depression.Palkovic B, Marchenko V, Zuperku EJ, Stuth EAE, Stucke AG. Palkovic B, et al. Physiology (Bethesda). 2020 Nov 1;35(6):391-404. doi: 10.1152/physiol.00015.2020. Physiology (Bethesda). 2020. PMID: 33052772 Free PMC article. Review.
- Remote, Automated, and MRI-Compatible Administration of Interoceptive Inspiratory Resistive Loading.Rieger SW, Stephan KE, Harrison OK. Rieger SW, et al. Front Hum Neurosci. 2020 May 12;14:161. doi: 10.3389/fnhum.2020.00161. eCollection 2020. Front Hum Neurosci. 2020. PMID: 32477083 Free PMC article.
-
- Bingel U., Wanigasekera V., Wiech K., Ni Mhuircheartaigh R., Lee M.C., Ploner M., Tracey I. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci. Transl. Med. 2011;3:70ra14. - PubMed
-
- Bond A., Lader M. Use of analog scales in rating subjective feelings. Br. J. Med. Psychol. 1974;47:211–218.
-
- Brooks J.C., Beckmann C.F., Miller K.L., Wise R.G., Porro C.A., Tracey I., Jenkinson M. Physiological noise modelling for spinal functional magnetic resonance imaging studies. Neuroimage. 2008;39:680–692. - PubMed
- Randomized Controlled Trial
- Adult
- Analgesics, Opioid / pharmacology*
- Brain / drug effects*
- Conditioning, Classical / drug effects*
- Double-Blind Method
- Dyspnea / psychology*
- Female
- Functional Neuroimaging
- Humans
- Magnetic Resonance Imaging
- Male
- Piperidines / pharmacology*
- Remifentanil
- Analgesics, Opioid
- Piperidines
- Remifentanil
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
![Fig. 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5391989/bin/gr4.jpg)
![Fig. 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5391989/bin/gr5.jpg)
References
- Aslan S., Xu F., Wang P.L., Uh J., Yezhuvath U.S., van Osch M., Lu H. Estimation of labeling efficiency in pseudocontinuous arterial spin labeling. Magn. Reson. Med. 2010;63:765–771.
- Atlas L.Y., Bolger N., Lindquist M.A., Wager T.D. Brain mediators of predictive cue effects on perceived pain. J. Neurosci. 2010;30:12964–12977.
- Bingel U., Wanigasekera V., Wiech K., Ni Mhuircheartaigh R., Lee M.C., Ploner M., Tracey I. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci. Transl. Med. 2011;3:70ra14.
- Bond A., Lader M. Use of analog scales in rating subjective feelings. Br. J. Med. Psychol. 1974;47:211–218.
- Brooks J.C., Beckmann C.F., Miller K.L., Wise R.G., Porro C.A., Tracey I., Jenkinson M. Physiological noise modelling for spinal functional magnetic resonance imaging studies. Neuroimage. 2008;39:680–692.
- Brooks J.C., Faull O.K., Pattinson K.T., Jenkinson M. Physiological noise in brainstem FMRI. Front. Hum. Neurosci. 2013;7:623.
- Cohen E.R., Ugurbil K., Kim S.G. Effect of basal conditions on the magnitude and dynamics of the blood oxygenation level-dependent fMRI response. J. Cereb. Blood Flow Metab. 2002;22:1042–1053.
- Craig A.D.B. How do you feel--now? The anterior insula and human awareness. Nat. Rev. Neurosci. 2009;10:59–70.
- Currow D.C., Abernethy A.P., Allcroft P., Banzett R.B., Bausewein C., Booth S., Carrieri-Kohlman V., Davidson P., Disler R., Donesky D., Dudgeon D., Ekstrom M., Farquhar M., Higginson I., Janssen D., Jensen D., Jolley C., Krajnik M., Laveneziana P., McDonald C., Maddocks M., Morelot-Panzini C., Moxham J., Mularski R.A., Noble S., O'Donnell D., Parshall M.B., Pattinson K., Phillips J., Ross J., Schwartzstein R.M., Similowski T., Simon S.T., Smith T., Wells A., Yates P., Yorke J., Johnson M.J. The need to research refractory breathlessness. Eur. Respir. J. 2016;47:342–343.
- Currow D.C., Quinn S., Greene A., Bull J., Johnson M.J., Abernethy A.P. The longitudinal pattern of response when morphine is used to treat chronic refractory dyspnea. J. Palliat. Med. 2013;16:881–886.
- De Peuter S., Van Diest I., Lemaigre V., Li W., Verleden G., Demedts M., Van den Bergh O. Can subjective asthma symptoms be learned? Psychosom. Med. 2005;67:454–461.
- De Peuter S., Van Diest I., Lemaigre V., Verleden G., Demedts M., Van den Bergh O. Dyspnea: the role of psychological processes. Clin. Psychol. Rev. 2004;24:557–581.
- Eichenbaum H., Lipton P.A. Towards a functional organization of the medial temporal lobe memory system: role of the parahippocampal and medial entorhinal cortical areas. Hippocampus. 2008;18:1314–1324.
- Eippert F., Bingel U., Schoell E., Yacubian J., Buchel C. Blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans. J. Neurosci. 2008;28:5465–5472.
- Eippert F., Bingel U., Schoell E.D., Yacubian J., Klinger R., Lorenz J., Buchel C. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009;63:533–543.
- Ekstrom M.P., Abernethy A.P., Currow D.C. The management of chronic breathlessness in patients with advanced and terminal illness. BMJ. 2015;349:g7617.
- Fanselow M.S. Pavlovian conditioning, negative feedback, and blocking: mechanisms that regulate association formation. Neuron. 1998;20:625–627.
- Faull O.K., Jenkinson M., Clare S., Pattinson K.T. Functional subdivision of the human periaqueductal grey in respiratory control using 7 tesla fMRI. Neuroimage. 2015;113:356–364.
- Faull O.K., Jenkinson M., Ezra M., Pattinson K.T. Conditioned respiratory threat in the subdivisions of the human periaqueductal gray. Elife. 2016:5. pii: e12047.
- Favaroni Mendes L.A., Menescal-de-Oliveira L. Role of cholinergic, opioidergic and GABAergic neurotransmission of the dorsal hippocampus in the modulation of nociception in guinea pigs. Life Sci. 2008;83:644–650.
- Glover G.H., Li T.Q., Ress D. Image-based method for retrospective correction of physiological motion effects in fMRI: retroicor. Magn. Reson. Med. 2000;44:162–167.
- Griffanti L., Salimi-Khorshidi G., Beckmann C.F., Auerbach E.J., Douaud G., Sexton C.E., Zsoldos E., Ebmeier K.P., Filippini N., Mackay C.E., Moeller S., Xu J., Yacoub E., Baselli G., Ugurbil K., Miller K.L., Smith S.M. ICA-based artefact removal and accelerated fMRI acquisition for improved resting state network imaging. Neuroimage. 2014;95:232–247.
- Handwerker D.A., Ollinger J.M., D'Esposito M. Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses. Neuroimage. 2004;21:1639–1651.
- Harvey A.K., Pattinson K.T., Brooks J.C., Mayhew S.D., Jenkinson M., Wise R.G. Brainstem functional magnetic resonance imaging: disentangling signal from physiological noise. J. Magn. Reson. Imaging. 2008;28:1337–1344.
- Hayen A., Herigstad M., Kelly M., Okell T.W., Murphy K., Wise R.G., Pattinson K.T. The effects of altered intrathoracic pressure on resting cerebral blood flow and its response to visual stimulation. Neuroimage. 2012;66:479–488.
- Hayen A., Herigstad M., Pattinson K.T. Understanding dyspnea as a complex individual experience. Maturitas. 2013;76:45–50.
- Hayen A., Herigstad M., Wiech K., Pattinson K.T. Subjective evaluation of experimental dyspnoea--effects of isocapnia and repeated exposure. Respir. Physiol. Neurobiol. 2015;208:21–28.
- Herigstad M., Hayen A., A., R., Pattinson K.T.S. Development of a dyspnoea word cue set for studies of emotional processing in COPD. Respir. Physiol. Neurobiol. 2016;223:37–42.
- Herigstad M., Hayen A., Evans E., Hardinge F.M., Davies R.J., Wiech K., Pattinson K.T. Dyspnea-related cues engage the prefrontal cortex: evidence from functional brain imaging in COPD. Chest. 2015;148:953–961.
- Herigstad M., Hayen A., Wiech K., Pattinson K.T. Dyspnoea and the brain. Respir. Med. 2011;105:809–817.
- Janssens T., Verleden G., De Peuter S., Van Diest I., Van den Bergh O. Inaccurate perception of asthma symptoms: a cognitive-affective framework and implications for asthma treatment. Clin. Psychol. Rev. 2009;29:317–327.
- Jenkinson M., Bannister P., Brady M., Smith S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage. 2002;17:825–841.
- Jones A.K., Qi L.Y., Fujirawa T., Luthra S.K., Ashburner J., Bloomfield P., Cunningham V.J., Itoh M., Fukuda H., Jones T. In vivo distribution of opioid receptors in man in relation to the cortical projections of the medial and lateral pain systems measured with positron emission tomography. Neurosci. Lett. 1991;126:25–28.
- Kelly R.E., Jr., Alexopoulos G.S., Wang Z., Gunning F.M., Murphy C.F., Morimoto S.S., Kanellopoulos D., Jia Z., Lim K.O., Hoptman M.J. Visual inspection of independent components: defining a procedure for artifact removal from fMRI data. J. Neurosci. Methods. 2010;189:233–245.
- LaBar K.S., LeDoux J.E., Spencer D.D., Phelps E.A. Impaired fear conditioning following unilateral temporal lobectomy in humans. J. Neurosci. 1995;15:6846–6855.
- Lansing R.W., Gracely R.H., Banzett R.B. The multiple dimensions of dyspnea: review and hypotheses. Respir. Physiol. Neurobiol. 2009;167:53–60.
- Leknes S., Tracey I. A common neurobiology for pain and pleasure. Nat. Rev. Neurosci. 2008;9:314–320.
- Leppa M., Korvenoja A., Carlson S., Timonen P., Martinkauppi S., Ahonen J., Rosenberg P.H., Aronen H.J., Kalso E. Acute opioid effects on human brain as revealed by functional magnetic resonance imaging. Neuroimage. 2006;31:661–669.
- Ley R. Respiratory psychophysiology and behavior modification. Behav. Modif. 2001;25:491–494.
- Luchtmann M., Jachau K., Tempelmann C., Bernarding J. Alcohol induced region-dependent alterations of hemodynamic response: implications for the statistical interpretation of pharmacological fMRI studies. Exp. Brain Res. 2010;204:1–10.
- MacIntosh B.J., Pattinson K.T., Gallichan D., Ahmad I., Miller K.L., Feinberg D.A., Wise R.G., Jezzard P. Measuring the effects of remifentanil on cerebral blood flow and arterial arrival time using 3D GRASE MRI with pulsed arterial spin labelling. J. Cereb. Blood Flow Metab. 2008;28:1514–1522.
- McGaraughty S., Heinricher M.M. Microinjection of morphine into various amygdaloid nuclei differentially affects nociceptive responsiveness and RVM neuronal activity. Pain. 2002;96:153–162.
- McNally G.P., Pigg M., Weidemann G. Blocking, unblocking, and overexpectation of fear: a role for opioid receptors in the regulation of Pavlovian association formation. Behav. Neurosci. 2004;118:111–120.
- Minto C.F., Schnider T.W., Egan T.D., Youngs E., Lemmens H.J., Gambus P.L., Billard V., Hoke J.F., Moore K.H., Hermann D.J., Muir K.T., Mandema J.W., Shafer S.L. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology. 1997;86:10–23.
- Minto C.F., Schnider T.W., Shafer S.L. Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology. 1997;86:24–33.
- Mitsis G.D., Governo R.J., Rogers R., Pattinson K.T. The effect of remifentanil on respiratory variability, evaluated with dynamic modeling. J. Appl. Physiol. 2009;106:1038–1049.
- Muthukumaraswamy S.D., Evans C.J., Edden R.A., Wise R.G., Singh K.D. Individual variability in the shape and amplitude of the BOLD-HRF correlates with endogenous GABAergic inhibition. Hum. Brain Mapp. 2012;33:455–465.
- Okell T.W., Chappell M.A., Kelly M.E., Jezzard P. Cerebral blood flow quantification using vessel-encoded arterial spin labeling. J. Cereb. Blood Flow Metab. 2013;33:1716–1724.
- Oxberry S.G., Bland J.M., Clark A.L., Cleland J.G., Johnson M.J. Repeat dose opioids may be effective for breathlessness in chronic heart failure if given for long enough. J. Palliat. Med. 2013;16:250–255.
- Oxley R., Macnaughton J. Inspiring change: humanities and social science insights into the experience and management of breathlessness. Curr. Opin. Support Palliat. Care. 2016;10:256–261.
- Palermo S., Benedetti F., Costa T., Amanzio M. Pain anticipation: an activation likelihood estimation meta-analysis of brain imaging studies. Hum. Brain Mapp. 2015;36:1648–1661.
- Pattinson K. Functional brain imaging in respiratory medicine. Thorax. 2015;70:598–600.
- Pattinson K.T. Opioids and the control of respiration. Br. J. Anaesth. 2008;100:747–758.
- Pattinson K.T., Governo R.J., MacIntosh B.J., Russell E.C., Corfield D.R., Tracey I., Wise R.G. Opioids depress cortical centers responsible for the volitional control of respiration. J. Neurosci. 2009;29:8177–8186.
- Pattinson K.T., Johnson M.J. Neuroimaging of central breathlessness mechanisms. Curr. Opin. Support Palliat. Care. 2014;8:225–233.
- Pattinson K.T., Rogers R., Mayhew S.D., MacIntosh B.J., Lee M.C., Wise R.G. Remifentanil-induced cerebral blood flow effects in normal humans: dose and ApoE genotype. Anesth. Analg. 2008;106(347):347–348.
- Pattinson K.T., Rogers R., Mayhew S.D., Tracey I., Wise R.G. Pharmacological FMRI: measuring opioid effects on the BOLD response to hypercapnia. J. Cereb. Blood Flow Metab. 2007;27:414–423.
- Pattinson K.T., Wise R.G. Imaging the respiratory effects of opioids in the human brain. Adv. Exp. Med. Biol. 2016;903:145–156.
- Peiffer C. Morphine-induced relief of dyspnea: what are the mechanisms? Am. J. Respir. Crit. Care Med. 2011;184:867–869.
- Petrovic P., Kalso E., Petersson K.M., Ingvar M. Placebo and opioid analgesia-- imaging a shared neuronal network. Science. 2002;295:1737–1740.
- Phelps E.A. Human emotion and memory: interactions of the amygdala and hippocampal complex. Curr. Opin. Neurobiol. 2004;14:198–202.
- Phelps E.A., LeDoux J.E. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron. 2005;48:175–187.
- Ploner M., Lee M.C., Wiech K., Bingel U., Tracey I. Prestimulus functional connectivity determines pain perception in humans. Proc. Natl. Acad. Sci. USA. 2010;107:355–360.
- Price D.D., Von der Gruen A., Miller J., Rafii A., Price C. A psychophysical analysis of morphine analgesia. Pain. 1985;22:261–269.
- Radloff L.S. The CES-D scale: a self-report depression scale for research in the general population. Appl. Psychol. Meas. 1977;1:385–401.
- Ray W.A., Chung C.P., Murray K.T., Hall K., Stein C.M. Prescription of long-acting opioids and mortality in patients with chronic noncancer pain. Jama. 2016;315:2415–2423.
- Robertson J.A., Purple R.J., Cole P., Zaiwalla Z., Wulff K., Pattinson K.T. Sleep disturbance in patients taking opioid medication for chronic back pain. Anaesthesia. 2016;71:1296–1307.
- Rocker G.M., Simpson A.C., Joanne Young B., Horton R., Sinuff T., Demmons J., Margaret Donahue M.M., Hernandez P., Marciniuk D. Opioid therapy for refractory dyspnea in patients with advanced chronic obstructive pulmonary disease: patients' experiences and outcomes. CMAJ Open. 2013;1:E27–E36.
- Salimi-Khorshidi G., Douaud G., Beckmann C.F., Glasser M.F., Griffanti L., Smith S.M. Automatic denoising of functional MRI data: combining independent component analysis and hierarchical fusion of classifiers. Neuroimage. 2014;90:449–468.
- Sandkühler J., Lee J. How to erase memory traces of pain and fear. Trends Neurosci. 2013;36:343–352.
- Sesack S.R., Grace A.A. Cortico-Basal Ganglia reward network: microcircuitry. Neuropsychopharmacology. 2010;35:27–47.
- Smith S.M. Fast robust automated brain extraction. Hum. Brain Mapp. 2002;17:143–155.
- Spielberger, C.D., 2010. State-Trait Anxiety Inventory. In: The Corsini Encyclopedia of Psychology. John Wiley & Sons, Inc.
- Tyrer P., Eilenberg T., Fink P., Hedman E., Tyrer H. Health anxiety: the silent, disabling epidemic. BMJ. 2016;353:i2250.
- Vozoris N.T., Wang X., Fischer H.D., Bell C.M., O'Donnell D.E., Austin P.C., Stephenson A.L., Gill S.S., Rochon P.A. Incident opioid drug use and adverse respiratory outcomes among older adults with COPD. Eur. Respir. J. 2016;48:683–693.
- Wanigasekera V., Lee M.C., Rogers R., Hu P., Tracey I. Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans. J. Neurosci. 2011;31:2835–2842.
- Wanigasekera V., Lee M.C., Rogers R., Kong Y., Leknes S., Andersson J., Tracey I. Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects. Proc. Natl. Acad. Sci. USA. 2012;109:17705–17710.
- Wiech K., Ploner M., Tracey I. Neurocognitive aspects of pain perception. Trends Cogn. Sci. 2008;12:306–313.
- Wiech K., Tracey I. The influence of negative emotions on pain: behavioral effects and neural mechanisms. Neuroimage. 2009;47:987–994.
- Winkler A.M., Ridgway G.R., Webster M.A., Smith S.M., Nichols T.E. Permutation inference for the general linear model. Neuroimage. 2014;92:381–397.
- Wise R.G., Pattinson K.T., Bulte D.P., Chiarelli P.A., Mayhew S.D., Balanos G.M., O'Connor D.F., Pragnell T.R., Robbins P.A., Tracey I., Jezzard P. Dynamic forcing of end-tidal carbon dioxide and oxygen applied to functional magnetic resonance imaging. J. Cereb. Blood Flow Metab. 2007;27:1521–1532.
- Wise R.G., Rogers R., Painter D., Bantick S., Ploghaus A., Williams P., Rapeport G., Tracey I. Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil. Neuroimage. 2002;16:999–1014.
- Wise R.G., Williams P., Tracey I. Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain. Neuropsychopharmacology. 2004;29:626–635.
- Woolrich M.W., Behrens T.E., Smith S.M. Constrained linear basis sets for HRF modelling using Variational Bayes. Neuroimage. 2004;21:1748–1761.
- Woolrich M.W., Behrens T.E.J., Beckmann C.F., Jenkinson M., Smith S.M. Multilevel linear modelling for FMRI group analysis using Bayesian inference. Neuroimage. 2004;21:1732–1747.
- Zaman J., Vlaeyen J.W., Van Oudenhove L., Wiech K., Van Diest I. Associative fear learning and perceptual discrimination: a perceptual pathway in the development of chronic pain. Neurosci. Biobehav. Rev. 2015;51:118–125.
- Zubieta J.K., Smith Y.R., Bueller J.A., Xu Y., Kilbourn M.R., Jewett D.M., Meyer C.R., Koeppe R.A., Stohler C.S. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001;293:311–315.
Source: PubMed