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Central sensitisation describes how nociceptive circuits amplify their gain. It does not, on its own, explain why that amplification becomes permanent, why it co-emerges systematically with fatigue and autonomic dysregulation, or why its epidemiology is stratified by sex in ways that differ qualitatively rather than quantitatively. The Informational Blackout framework proposes that chronic pain and fatigue are not malfunctions but appropriate responses from a self-maintaining system that has lost the biological infrastructure on which it was built to depend. The upstream driver is structural degradation of the signal architecture by the modern environment, mediated through SOCS3-driven multichannel transduction collapse and a convergent five-arm ionic setpoint failure that inscribes pain as a stable engram. The framework is offered as an upstream extension of central sensitisation; it grades its own evidence explicitly and generates falsifiable predictions that reorient therapeutic logic from nociceptive suppression toward signal architecture restoration.<\/jats:p>","DOI":"10.3389\/fpain.2026.1896306","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T12:39:21Z","timestamp":1786538361000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The Informational Blackout chronic pain and fatigue as rational outputs of a brain operating on degraded biological signals"],"prefix":"10.3389","volume":"7","author":[{"given":"Carla","family":"Pandolfi-Cuadrado","sequence":"first","affiliation":[{"name":"Miguel Hern\u00e1ndez University of Elche","place":["Elche, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","year":""},{"key":"B2","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/nrn.2016.162","article-title":"Structural plasticity and reorganisation in chronic pain","volume":"18","author":"Kuner","year":"2017","journal-title":"Nat Rev Neurosci"},{"key":"B3","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.pneurobio.2008.09.018","article-title":"Towards a theory of chronic pain","volume":"87","author":"Apkarian","year":"2009","journal-title":"Prog Neurobiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1038\/nature04223","article-title":"BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain","volume":"438","author":"Coull","year":"2005","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"4453","DOI":"10.1073\/pnas.0808180106","article-title":"Adverse metabolic and cardiovascular consequences of circadian misalignment","volume":"106","author":"Scheer","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1038\/s41593-020-0689-4","article-title":"A glycolytic shift in Schwann cells supports injured axons","volume":"23","author":"Babetto","year":"2020","journal-title":"Nat Neurosci"},{"key":"B7","doi-asserted-by":"publisher","first-page":"R316","DOI":"10.1016\/j.cub.2020.02.090","article-title":"Neuroscience: a chromatic retinal circuit encodes sunrise and sunset for the brain","volume":"30","author":"Rivera","year":"2020","journal-title":"Curr Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1111\/j.1751-1097.2008.00394.x","article-title":"Mitochondrial signaling in mammalian cells activated by red and near-IR radiation","volume":"84","author":"Karu","year":"2008","journal-title":"Photochem Photobiol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e70331","DOI":"10.1002\/alz.70331","article-title":"Gut-derived bacterial vesicles carrying LPS promote microglia-mediated synaptic pruning","volume":"21","author":"Zhao","year":"2025","journal-title":"Alzheimers Demen"},{"key":"B10","doi-asserted-by":"publisher","first-page":"102180","DOI":"10.1016\/j.molmet.2025.102180","article-title":"Gut microbiota-derived extracellular vesicles exhibit diurnal regulation and activate hepatic gluconeogenesis","volume":"98","author":"Tan","year":"2025","journal-title":"Mol Metab"},{"key":"B11","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1007\/s00125-021-05643-9","article-title":"The influence of bright and dim light on substrate metabolism depends on time of day","volume":"65","author":"Harmsen","year":"2022","journal-title":"Diabetologia"},{"key":"B12","doi-asserted-by":"publisher","first-page":"15932","DOI":"10.1073\/pnas.0904747106","article-title":"Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake","volume":"106","author":"Olofsson","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B13","doi-asserted-by":"publisher","first-page":"103500","DOI":"10.1016\/j.mcn.2020.103500","article-title":"Leptin stimulates synaptogenesis in hippocampal neurons via KLF4 and SOCS3 inhibition of STAT3 signaling","volume":"106","author":"Sahin","year":"2020","journal-title":"Mol Cell Neurosci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.36726","article-title":"The adipocyte hormone leptin sets the emergence of hippocampal inhibition in mice. 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