{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:45:06Z","timestamp":1789055106580,"version":"build-2803163510"},"reference-count":99,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Phantom limb pain (PLP) is a frequent and often persistent consequence of limb amputation, characterized by pain perceived in the absent limb. Despite decades of research, its biological basis remains incompletely understood, and available treatments often provide inconsistent relief. This reflects the complex and heterogeneous nature of phantom limb pain, which cannot be explained by a single anatomical site or pathological process. Current evidence suggests that phantom limb pain emerges from the interaction of changes occurring at multiple levels of the nervous system. Peripheral nerve injury associated with amputation induces molecular and cellular alterations that may influence early nociceptive signaling. These changes can interact with adaptive and maladaptive responses within the spinal cord, including altered synaptic transmission and neuron\u2013glia interactions, which may facilitate sustained amplification of pain-related signals. At supraspinal levels, long-term adaptations within distributed neural networks involved in sensory, motor, and affective processing may contribute to the persistence of pain perceptions in the absence of ongoing peripheral input. Immune-related signaling and long-term regulation of gene expression further modulate these processes and may contribute to inter-individual variability. In this narrative review, we synthesize current experimental and clinical evidence addressing the molecular and cellular processes associated with phantom limb pain following lower limb amputation. Findings are integrated across peripheral, spinal, and supraspinal levels, with consideration of immune-related and regulatory influences. By highlighting areas of convergence, uncertainty, and existing knowledge gaps, this review aims to provide a coherent biological framework that may support future experimental and translational research in this challenging field.<\/jats:p>","DOI":"10.3390\/ijms27052107","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T15:05:27Z","timestamp":1771945527000},"page":"2107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["From Amputation to Persistent Pain: A Review of Molecular and Cellular Processes in Phantom Limb Pain"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4466-6360","authenticated-orcid":false,"given":"Catalin-Bogdan","family":"Satala","sequence":"first","affiliation":[{"name":"\u201cDun\u0103rea de Jos\u201d University of Galati, Faculty of Medicine and Pharmacy, Medical and Pharmaceutical Research Center, 800008 Galati, Romania"},{"name":"Department of Pathology, Clinical County Emergency Hospital, 810325 Br\u0103ila, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Onofrei (Popa)","sequence":"additional","affiliation":[{"name":"\u201cDun\u0103rea de Jos\u201d University of Galati, Faculty of Medicine and Pharmacy, Medical and Pharmaceutical Research Center, 800008 Galati, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5518-5864","authenticated-orcid":false,"given":"Oana","family":"Vr\u00eenceanu","sequence":"additional","affiliation":[{"name":"Doctoral School, \u201cGeorge Emil Palade\u201d University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Mihalache","sequence":"additional","affiliation":[{"name":"\u201cDun\u0103rea de Jos\u201d University of Galati, Faculty of Medicine and Pharmacy, Medical and Pharmaceutical Research Center, 800008 Galati, Romania"},{"name":"Department of Pathology, Clinical County Emergency Hospital, 810325 Br\u0103ila, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/S1474-4422(02)00074-1","article-title":"Phantom-limb pain: Characteristics, causes, and treatment","volume":"1","author":"Flor","year":"2002","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0304-3959(00)00264-5","article-title":"Phantom pain and phantom sensations in upper limb amputees: An epidemiological study","volume":"87","author":"Kooijman","year":"2000","journal-title":"Pain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1177\/2049463717736492","article-title":"Chronic post-amputation pain: Peri-operative management\u2014Review","volume":"11","author":"Srivastava","year":"2017","journal-title":"Br. 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