{"doi":"10.1113/jp272599","title":"Secondary hyperalgesia is mediated by heat‐insensitive A‐fibre nociceptors","abstract":"<jats:sec><jats:title>Key points</jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>It is believed that secondary hyperalgesia (the increased sensitivity to mechanical nociceptive stimuli that develops after cutaneous tissue injury in the surrounding uninjured skin) is mediated by a subclass of nociceptors: the slowly adapting A‐fibre mechano‐heat nociceptors (AMH‐type I). Here we tested this hypothesis.</jats:p></jats:list-item>\n<jats:list-item><jats:p>By using intense long‐lasting heat stimuli, which are known to activate these slowly adapting AMH‐type I nociceptors, we show that the perceived intensity elicited by these stimuli is <jats:italic>not</jats:italic> increased in the area of secondary hyperalgesia.</jats:p></jats:list-item>\n<jats:list-item><jats:p>Moreover, we show that during an A‐fibre nerve conduction block the perception elicited by the long‐lasting heat stimuli is significantly reduced in a time window that matches the response profile of the AMH‐type I nociceptors.</jats:p></jats:list-item>\n<jats:list-item><jats:p>AMH‐type I nociceptors contribute to the perception of sustained heat, but they do not mediate secondary hyperalgesia. Therefore, we propose that secondary hyperalgesia is mediated by high threshold mechanoreceptors.</jats:p></jats:list-item>\n</jats:list></jats:p></jats:sec><jats:sec><jats:title>Abstract</jats:title><jats:p>Secondary hyperalgesia refers to the increase in sensitivity to mechanical nociceptive stimuli delivered outside the area of tissue injury. Previous studies have suggested that secondary hyperalgesia is mediated by a specific class of myelinated nociceptors: slowly adapting A‐fibre mechano‐ and heat‐sensitive (AMH) type I nociceptors. Here, we tested this hypothesis by examining whether long‐lasting heat stimuli, which are known to activate AMH‐type I nociceptors, elicit enhanced responses when delivered to the area of secondary hyperalgesia induced by high frequency electrical stimulation of the skin (HFS). Before and 20 min after HFS, sustained 30 s radiant heat stimuli were delivered to the area of increased mechanical pinprick sensitivity while participants continuously rated intensity of perception using an online visual analog scale (0–100 mm). After HFS, no significant enhancement of heat perception was observed in the area of increased pinprick sensitivity. To establish that myelinated nociceptors actually contribute to the perception of sustained heat, we conducted a second experiment in which sustained heat stimuli were presented before and during an A‐fibre nerve conduction block, achieved by applying a rubber band with weights which compresses the superficial radial nerve against the radius. During the block, heat perception was significantly reduced 17–33 s after the onset of the heat stimulus (before: mean = 53 mm, during: mean = 31 mm; <jats:italic>P</jats:italic> = 0.03), matching the response profile of AMH‐type I nociceptors. These results support the notion that AMH‐type I nociceptors contribute to the perception of sustained heat, but also show that these afferents do not mediate secondary hyperalgesia.</jats:p></jats:sec>","journal":"The Journal of Physiology","year":2016,"id":35267,"datarank":1.6379643979159306,"base_score":4.060443010546419,"endowment":4.060443010546419,"self_citation_contribution":0.6090664515819629,"citation_network_contribution":1.0288979463339678,"self_endowment_contribution":0.6090664515819629,"citer_contribution":1.0288979463339678,"corpus_percentile":null,"corpus_rank":null,"citation_count":57,"citer_count":33,"citers_with_citation_signal":22,"citers_with_endowment":22,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":181000,"name":"Cédric Lenoir","orcid":null,"position":1,"is_corresponding":false},{"id":181001,"name":"André Mouraux","orcid":null,"position":2,"is_corresponding":false},{"id":180999,"name":"Emanuel N. van den Broeke","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":4.060443010546419,"endowment":4.060443010546419,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"27377467","pmcid":null,"openalex_id":"https://openalex.org/W2460583745","authors":[],"funders":[{"funder_name":"European Research Council","grant_id":"PROBING PAIN 336130","title":null},{"funder_name":"European Commission","grant_id":"336130","title":"Multimodal functional neuroimaging techniques to probe the representation of pain in the human brain"}],"total_grants":2,"fwci":3.5565,"citation_percentile":0.92719059,"influential_citations":1,"citation_trend":[{"year":2016,"count":2},{"year":2017,"count":3},{"year":2018,"count":10},{"year":2019,"count":3},{"year":2020,"count":1},{"year":2021,"count":7},{"year":2022,"count":5},{"year":2023,"count":2},{"year":2024,"count":12},{"year":2025,"count":8},{"year":2026,"count":4}],"oa_status":"bronze","license":"Wiley Online Library User Agreement","oa_locations":[{"url":"https://physoc.onlinelibrary.wiley.com/doi/pdfdirect/10.1113/JP272599","host_type":"journal"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108905","host_type":"GREEN"},{"url":"https://physoc.onlinelibrary.wiley.com/doi/pdfdirect/10.1113/JP272599","host_type":"publisher"},{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1113%2FJP272599","host_type":"publisher"},{"url":"https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP272599","host_type":"publisher"},{"url":"https://doi.org/10.1113/jp272599","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/27377467","host_type":"repository"},{"url":"http://hdl.handle.net/2078.1/180026","host_type":"repository"},{"url":"http://hdl.handle.net/2078.1/194782","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5108905","host_type":"repository"},{"url":"https://dx.doi.org/10.1113/jp272599","host_type":""},{"url":"https://hdl.handle.net/2078.1/194782","host_type":""},{"url":"http://dx.doi.org/10.1113/JP272599","host_type":""}],"fields_of_study":["Pain Mechanisms and Treatments","Pain Management and Placebo Effect","Acupuncture Treatment Research Studies","Chemistry","Medicine","Biology","0301 basic medicine","03 medical and health sciences","0302 clinical medicine","Adult","Electric Stimulation","Female","Hot Temperature","Humans","Hyperalgesia","Male","Mechanoreceptors","Nerve Fibers, Myelinated","Neural Conduction","Nociceptors","Pain","Pain Measurement","Physical Stimulation","Skin","Young Adult"],"mesh_terms":["Adult","Electric Stimulation","Female","Hot Temperature","Humans","Hyperalgesia","Male","Mechanoreceptors","Nerve Fibers, Myelinated","Neural Conduction","Nociceptors","Pain","Pain Measurement","Physical Stimulation","Skin","Young Adult"],"keywords":["Nociceptor","Hyperalgesia","Nociception","Radiant heat","Stimulation","Neuroscience","Chemistry","Medicine","Endocrinology","Internal medicine","Psychology","Receptor","Secondary Hyperalgesia","Amh-type I","Sustained Heat","Adult","Male","Hot Temperature","Neural Conduction","Nociceptors","Pain","Nerve Fibers, Myelinated","Electric Stimulation","Young Adult","Physical Stimulation","Humans","Female","Mechanoreceptors","Pain Measurement","Skin"],"sdg_mappings":[{"sdg_number":12,"sdg_label":"12. 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