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Neuropathic pain is a chronic pain state caused by primary damage or dysfunction of the nervous system; however, the details of the molecular mechanisms have not yet been fully elucidated. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect signals released by injured tissues and respond to these damage signals. TRP channels are similar to the voltage-gated potassium channels or nucleotide-gated channels that participate in calcium and magnesium homeostasis. TRP channels allowing calcium to penetrate into nerve terminals can activate apoptosis, leading to nerve terminal destruction. Further, some TRPs are activated by acid and reactive oxygen species (ROS). ROS are mainly produced in the mitochondrial respiratory chain, and an increase in ROS production and\/or a decrease in the antioxidant network may induce oxidative stress (OS). Depending on the OS levels, they can promote cellular proliferation and\/or cell degeneration or death. Previous studies have indicated that proinflammatory cytokines, such as tumor necrosis factor-\u03b1 (TNF-\u03b1), play an important role in the peripheral mediation of neuropathic pain. This article aims to perform a review of the involvement of apoptosis in pain, particularly the role of OS and neuroinflammation, and the clinical relevance of this knowledge. The potential discovery of new biomarkers and therapeutic targets can result in the development of more effective and targeted drugs to treat chronic pain, namely neuropathic pain. Highlights: Oxidative stress and neuroinflammation can activate cell signaling pathways that can lead to nerve terminal destruction by apoptosis. These could constitute potential new pain biomarkers and targets for therapy in neuropathic pain.<\/jats:p>","DOI":"10.3390\/biomedicines10061255","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T07:05:07Z","timestamp":1653635107000},"page":"1255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Apoptosis and (in) Pain\u2014Potential Clinical Implications"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6623-7420","authenticated-orcid":false,"given":"Hugo","family":"Ribeiro","sequence":"first","affiliation":[{"name":"Community Support Team in Palliative Care\u2013Group of Health Centers Gaia, 4430-043 Vila Nova de Gaia, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environment Genetics and Oncobiology (CIMAGO), FMUC, 3000-548 Coimbra, Portugal"},{"name":"Centro de Estudos e Desenvolvimento dos Cuidados Continuados e Paliativos da Faculdade de Medicina da Universidade de Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Programa Doutoral em Cuidados Paliativos da Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4142-4841","authenticated-orcid":false,"given":"Ana Bela","family":"Sarmento-Ribeiro","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environment Genetics and Oncobiology (CIMAGO), FMUC, 3000-548 Coimbra, Portugal"},{"name":"Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine, University of Coimbra, FMUC, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3000-548 Coimbra, Portugal"},{"name":"Centro Hospitalar e Universit\u00e1rio de Coimbra (CHUC), 3004-561 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2585-200X","authenticated-orcid":false,"given":"Jos\u00e9 Paulo","family":"Andrade","sequence":"additional","affiliation":[{"name":"Department of Biomedicine\u2013Unity of Anatomy, Faculty of Medicine of Universidade of Porto, 4200-319 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Mar\u00edlia","family":"Dourado","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environment Genetics and Oncobiology (CIMAGO), FMUC, 3000-548 Coimbra, Portugal"},{"name":"Centro de Estudos e Desenvolvimento dos Cuidados Continuados e Paliativos da Faculdade de Medicina da Universidade de Coimbra, 3000-548 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/sj.cdd.4401848","article-title":"The crucial role of neuronal plasticity in pain and cell death","volume":"13","author":"Corasaniti","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1016\/j.pain.2011.06.017","article-title":"A new definition of neuropathic pain","volume":"152","author":"Jensen","year":"2011","journal-title":"Pain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/j.pain.0000000000001365","article-title":"The IASP classification of chronic pain for ICD-11: Chronic neuropathic pain","volume":"160","author":"Scholz","year":"2019","journal-title":"Pain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.pain.2013.11.013","article-title":"Neuropathic pain in the general population: A systematic review of epidemiological studies","volume":"155","author":"Austin","year":"2014","journal-title":"Pain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105280","DOI":"10.1016\/j.phrs.2020.105280","article-title":"Neuroinflammation, oxidative stress and their interplay in neuropathic pain: Focus on specialized pro-resolving mediators and NADPH oxidase inhibitors as potential therapeutic strategies","volume":"162","author":"Pinho","year":"2020","journal-title":"Pharmacol. 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