{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:19:47Z","timestamp":1792001987605,"version":"4.4.0"},"reference-count":93,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Placebo and nocebo effects on pain provide a model for investigating how cognitive and contextual factors modulate the physiological processes underlying nociception and its regulation. However, existing accounts remain fragmented and lack a unifying mechanistic framework linking brain, behaviour and autonomic responses. Here, we synthesize evidence from neuroimaging, electrophysiology, pharmacological and experimental paradigms within a predictive processing framework, conceptualizing pain as an inferential process arising from the integration of top\u2010down predictions and bottom\u2010up nociceptive input weighted by their precision. Across studies, placebo analgesia is consistently associated with increased engagement of prefrontal\u2013cingulate circuits and descending modulatory pathways, including periaqueductal grey and rostral ventromedial medulla, alongside activation of opioidergic, dopaminergic and cannabinoid systems. In contrast, nocebo hyperalgesia involves increased activity in limbic\u2013interoceptive networks, recruitment of stress\u2010related systems and cholecystokinin\u2010mediated facilitation of nociceptive transmission. Within this framework, placebo and nocebo effects emerge as precision\u2010dependent modulations of predictive signals that shape both central processing and peripheral physiological outputs, including autonomic and neuroendocrine responses. We further identify methodological approaches to operationalize priors, precision and prediction errors, and discuss how inter\u2010individual variability may reflect differences in computational and physiological phenotypes. This integrative review offers a mechanistic bridge between cognitive context and physiological regulation, offering a novel perspective on how endogenous predictions can be harnessed to enhance treatment efficacy and mitigate adverse outcomes in clinical practice.<\/jats:p>","DOI":"10.1113\/ep093418","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T08:34:08Z","timestamp":1787906048000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Placebo and nocebo effects on pain through the lens of the predictive brain: Neurobiological mechanisms and translational implications"],"prefix":"10.1113","author":[{"given":"Denisa Adina","family":"Zamfira","sequence":"first","affiliation":[{"name":"Department of Neurosciences \u201cRita Levi Montalcini\u201d University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6723-3653","authenticated-orcid":false,"given":"Tommaso","family":"Fassina","sequence":"additional","affiliation":[{"name":"Department of Neurosciences \u201cRita Levi Montalcini\u201d University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamil","family":"Zaworski","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy John Paul II University  Bia\u0142a Podlaska Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Carlino","sequence":"additional","affiliation":[{"name":"Department of Neurosciences \u201cRita Levi Montalcini\u201d University of Turin  Turin Italy"},{"name":"Laboratorio di Neurobiologia Istituto Auxologico Italiano \u2010 IRCCS Ospedale S. Giuseppe  Piancavallo, Oggebbio Verbano\u2010Cusio\u2010Ossola Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1623-7681","authenticated-orcid":false,"given":"Giacomo","family":"Rossettini","sequence":"additional","affiliation":[{"name":"School of Physiotherapy University of Verona  Verona Italy"},{"name":"Department of Physiotherapy Faculty of Medicine, Health and Sports Universidad Europea de Madrid  Villaviciosa de Od\u00f3n Spain"},{"name":"Centre for PAIn Research Health Sciences University  Bournemouth UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.conb.2017.08.010","article-title":"With or without you: Predictive coding and Bayesian inference in the brain","volume":"46","author":"Aitchison L.","year":"2017","journal-title":"Current Opinion in Neurobiology"},{"key":"e_1_2_14_3_1","doi-asserted-by":"crossref","first-page":"5369","DOI":"10.1523\/JNEUROSCI.3010-18.2019","article-title":"Pupil\u2010linked arousal responds to unconscious surprisal","volume":"39","author":"Alamia A.","year":"2019","journal-title":"The Journal of Neuroscience"},{"key":"e_1_2_14_4_1","doi-asserted-by":"crossref","first-page":"969","DOI":"10.3389\/fphar.2019.00969","article-title":"Pain anticipation and nocebo\u2010related responses: A descriptive mini\u2010review of functional neuroimaging studies in normal subjects and precious hints on pain processing in the context of neurodegenerative disorders","volume":"10","author":"Amanzio M.","year":"2019","journal-title":"Frontiers in Pharmacology"},{"issue":"3","key":"e_1_2_14_5_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.pain.2009.07.010","article-title":"A systematic review of adverse events in placebo groups of anti\u2010migraine clinical trials","volume":"146","author":"Amanzio M.","year":"2009","journal-title":"Pain"},{"issue":"3","key":"e_1_2_14_6_1","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1002\/hbm.21471","article-title":"Activation likelihood estimation meta\u2010analysis of brain correlates of placebo analgesia in human experimental pain","volume":"34","author":"Amanzio M.","year":"2013","journal-title":"Human Brain Mapping"},{"issue":"1","key":"e_1_2_14_7_1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1146\/annurev-neuro-101822-122427","article-title":"How instructions, learning, and expectations shape pain and neurobiological responses","volume":"46","author":"Atlas L. 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