{"id":"03b81da4-dbb7-55bc-bf9f-18a81b19e641","stable_key":"c953cca8-774f-596d-b27a-f13c2c0b5fce:dhc-early-desensitisation","predicate":"induces","statement":"Desensitization and cross-tolerance occurred to the hypothermic effects of both capsaicin and dihydrocapsaicin in rats, and repeated administration of either compound resulted in chemogenic antinociception but not marked thermal antinociception.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"ddaac0aa-64ba-53ca-ac23-946f7af40176","mechanism_event_label":"Give it repeatedly and the cooling effect fades, and the fading carries across to capsaicin.","subject":{"id":"6259a8e0-9611-5f60-9e1b-53bbd8eb1afd","slug":"dihydrocapsaicin","display_name":"Dihydrocapsaicin","entity_type_key":"small_molecule"},"object":{"id":"ca87ae35-eb66-55c8-82c0-31a51c0fd2c2","slug":"cold-defence-response","display_name":"The cold-defence response that opposes induced cooling","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"ddaac0aa-64ba-53ca-ac23-946f7af40176","stable_key":"c953cca8-774f-596d-b27a-f13c2c0b5fce:dhc-early-desensitisation-event","event_type":"observed_intervention","label":"Give it repeatedly and the cooling effect fades, and the fading carries across to capsaicin.","description":"Desensitization and cross-tolerance occurred to the hypothermic effects of both capsaicin and dihydrocapsaicin in rats, and repeated administration of either compound resulted in chemogenic antinociception but not marked thermal antinociception.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"61257bae-68e0-5ae5-937a-da7fdd9c4301","slug":"core-body-temperature","display_name":"Core body temperature","entity_type_key":"cellular_process"},"role":"affected_endpoint","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"9cdd3a64-5185-5998-82a6-d25c8409b998","slug":"capsaicin","display_name":"Capsaicin","entity_type_key":"small_molecule"},"role":"cross_tolerant_compound","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"3c31407f-39a2-5261-bf31-f96b2055fa85","slug":"chemogenic-antinociception","display_name":"Chemogenic antinociception","entity_type_key":"cellular_process"},"role":"retained_effect","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"fd250c71-f059-56ac-b438-918b5ebb9696","slug":"thermal-antinociception","display_name":"Thermal antinociception","entity_type_key":"cellular_process"},"role":"absent_effect","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"6259a8e0-9611-5f60-9e1b-53bbd8eb1afd","slug":"dihydrocapsaicin","display_name":"Dihydrocapsaicin","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"ca87ae35-eb66-55c8-82c0-31a51c0fd2c2","slug":"cold-defence-response","display_name":"The cold-defence response that opposes induced cooling","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/dihydrocapsaicin-research/6184240.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"dbeb69d90d490215b73d7a6f70fab0043e16cfdc8659c0daa4fda2cc0a7f6eaa\", \"start_char\": 0, \"end_char\": 897, \"text_sha256\": \"dbeb69d90d490215b73d7a6f70fab0043e16cfdc8659c0daa4fda2cc0a7f6eaa\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Dose-ranging subcutaneous administration in rats with repeated dosing, antinociception testing and regional substance P measurement","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Dihydrocapsaicin 0.5 to 10 mg/kg subcutaneously, single and repeated, against capsaicin","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"The founding comparison. It is a 1982 study and the antinociception endpoints are behavioural, but it is the only record here that puts a number on how the two compounds differ on temperature.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin.","comparator":null,"unit":null,"notes":"","entity":{"slug":"dihydrocapsaicin","display_name":"Dihydrocapsaicin","entity_type_key":"small_molecule"}},{"dimension":"organism","value_text":"Rat","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Give it repeatedly and the cooling effect fades, and the fading carries across to capsaicin.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[dhc-p6184240] Dihydrocapsaicin-induced hypothermia and substance P depletion. (1982). https://pubmed.ncbi.nlm.nih.gov/6184240/ DOI: 10.1016/0014-2999(82)90263-1","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Whole body, dorsal root ganglia and spinal cord","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"1a8f499a-4d96-5a4f-8a13-0c22add29bc8","evidence_kind":"source_excerpt","locator":"Lines 192-203","start_line":192,"end_line":203,"excerpt":"### dhc-early-desensitisation\nDesensitization and cross-tolerance occurred to the hypothermic effects of both capsaicin and dihydrocapsaicin in rats, and repeated administration of either compound resulted in chemogenic antinociception but not marked thermal antinociception.\nCondition category: normal\nnutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin.\nplain_language: Give it repeatedly and the cooling effect fades, and the fading carries across to capsaicin.\norganism: Rat\ntissue_or_cell_type: Whole body, dorsal root ganglia and spinal cord\nexperimental_model: Dose-ranging subcutaneous administration in rats with repeated dosing, antinociception testing and regional substance P measurement\nlimitations: The founding comparison. It is a 1982 study and the antinociception endpoints are behavioural, but it is the only record here that puts a number on how the two compounds differ on temperature.\nexposure: Dihydrocapsaicin 0.5 to 10 mg/kg subcutaneously, single and repeated, against capsaicin\nevidence_span: {\"source_cache\": \"artifacts/dihydrocapsaicin-research/6184240.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"dbeb69d90d490215b73d7a6f70fab0043e16cfdc8659c0daa4fda2cc0a7f6eaa\", \"start_char\": 0, \"end_char\": 897, \"text_sha256\": \"dbeb69d90d490215b73d7a6f70fab0043e16cfdc8659c0daa4fda2cc0a7f6eaa\"}\n[dhc-p6184240] Dihydrocapsaicin-induced hypothermia and substance P depletion. (1982). https://pubmed.ncbi.nlm.nih.gov/6184240/ DOI: 10.1016/0014-2999(82)90263-1","model_system":"Dose-ranging subcutaneous administration in rats with repeated dosing, antinociception testing and regional substance P measurement","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [dhc-p6184240] Dihydrocapsaicin-induced hypothermia and substance P depletion. (1982). https://pubmed.ncbi.nlm.nih.gov/6184240/ DOI: 10.1016/0014-2999(82)90263-1","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"263a8425-969d-5a1b-8a9b-6101ba6a26a7","stable_key":"import-c953cca8-774f-596d-b27a-f13c2c0b5fce","title":"Dihydrocapsaicin: the second capsaicinoid, the hypothermia it is used to induce, what the gut and liver do to it, and what it does without TRPV1 (2026-09-21)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"97d90ff5dc65dc321068c3e2a0525585f32b2e17eb0c6bfa0d9ef26dc2d6c5a3","revision_id":"dbdc1ad7-a05a-579d-b2aa-c4348e3efc40","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"7a94d223-90ff-5ef6-96b2-1d675ffd6090","title":"Does the hypothermic effect of dihydrocapsaicin fade with repeated dosing?","kind":"contradiction","status":"open","why":"A 1982 rat study found that desensitization and cross-tolerance occurred to the hypothermic effects of both capsaicin and dihydrocapsaicin, which would make repeated use futile. A 2014 mouse study found the opposite, reporting that the hypothermic effect was not desensitised with repeated administration and was in fact augmented in aged animals. The designs are not equivalent: the first gave repeated subcutaneous boluses to rats, the second gave a loading dose followed by continuous infusion to mice, and thirty-two years separate them. Continuous infusion holds the receptor occupied rather than repeatedly re-stimulating it, which may be the whole difference, but no record here tests that. Which applies to a sustained clinical infusion is not established.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 03:40:20","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/7a94d223-90ff-5ef6-96b2-1d675ffd6090","sides":[{"conflict_id":"7a94d223-90ff-5ef6-96b2-1d675ffd6090","ordinal":0,"label":"Give it repeatedly and the cooling effect fades, and the fading carries across to capsaicin.","revision_id":"dbdc1ad7-a05a-579d-b2aa-c4348e3efc40","start_line":192,"end_line":203,"quote":"### dhc-early-desensitisation\nDesensitization and cross-tolerance occurred to the hypothermic effects of both capsaicin and dihydrocapsaicin in rats, and repeated administration of either compound resulted in chemogenic antinociception but not marked thermal antinociception.\nCondition category: normal\nnutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin.\nplain_language: Give it repeatedly and the cooling effect fades, and the fading carries across to capsaicin.\norganism: Rat\ntissue_or_cell_type: Whole body, dorsal root ganglia and spinal cord\nexperimental_model: Dose-ranging subcutaneous administration in rats with repeated dosing, antinociception testing and regional substance P measurement\nlimitations: The founding comparison. It is a 1982 study and the antinociception endpoints are behavioural, but it is the only record here that puts a number on how the two compounds differ on temperature.\nexposure: Dihydrocapsaicin 0.5 to 10 mg/kg subcutaneously, single and repeated, against capsaicin\nevidence_span: {\"source_cache\": \"artifacts/dihydrocapsaicin-research/6184240.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"dbeb69d90d490215b73d7a6f70fab0043e16cfdc8659c0daa4fda2cc0a7f6eaa\", \"start_char\": 0, \"end_char\": 897, \"text_sha256\": \"dbeb69d90d490215b73d7a6f70fab0043e16cfdc8659c0daa4fda2cc0a7f6eaa\"}\n[dhc-p6184240] Dihydrocapsaicin-induced hypothermia and substance P depletion. (1982). https://pubmed.ncbi.nlm.nih.gov/6184240/ DOI: 10.1016/0014-2999(82)90263-1","source_key":"import-c953cca8-774f-596d-b27a-f13c2c0b5fce","source_title":"Dihydrocapsaicin: the second capsaicinoid, the hypothermia it is used to induce, what the gut and liver do to it, and what it does without TRPV1 (2026-09-21)","claim_ids":["03b81da4-dbb7-55bc-bf9f-18a81b19e641"]},{"conflict_id":"7a94d223-90ff-5ef6-96b2-1d675ffd6090","ordinal":1,"label":"Given this way the cooling did not wear off with repetition, and it worked harder in old mice than young ones.","revision_id":"dbdc1ad7-a05a-579d-b2aa-c4348e3efc40","start_line":270,"end_line":281,"quote":"### dhc-no-desensitisation\nDihydrocapsaicin produced a dose-dependent drop in core temperature over 2 to 4 mg/kg subcutaneously, a loading dose followed by continuous infusion produced a rapid and prolonged drop of more than six hours within the therapeutic range of 32 to 34 degrees, and the hypothermic effect was augmented in aged mice and was not desensitised with repeated administration.\nCondition category: normal\nnutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin.\nplain_language: Given this way the cooling did not wear off with repetition, and it worked harder in old mice than young ones.\norganism: Mouse\ntissue_or_cell_type: Core temperature\nexperimental_model: Controlled prospective study in conscious unrestrained young and aged male mice with implanted thermocouples and wireless transponders\nlimitations: Includes aged animals, which most of this collection does not. Its finding that the effect does not desensitise is the direct opposite of the 1982 rat result and the two are recorded as conflicting.\nexposure: Dihydrocapsaicin 2 to 4 mg/kg subcutaneously, alone and combined with the TRPM8 inhibitor compound 5 at 20 to 30 mg/kg\nevidence_span: {\"source_cache\": \"artifacts/dihydrocapsaicin-research/24595220.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"f8844f6469d0412a4fabe00ebd706924083ebc2759c847bff9da104ae4404a87\", \"start_char\": 0, \"end_char\": 1882, \"text_sha256\": \"f8844f6469d0412a4fabe00ebd706924083ebc2759c847bff9da104ae4404a87\"}\n[dhc-p24595220] Transient receptor potential melastatin 8 channel inhibition potentiates the hypothermic response to transient receptor potential vanilloid 1 activation in the conscious mouse. (2014). https://pubmed.ncbi.nlm.nih.gov/24595220/ DOI: 10.1097/ccm.0000000000000229","source_key":"import-c953cca8-774f-596d-b27a-f13c2c0b5fce","source_title":"Dihydrocapsaicin: the second capsaicinoid, the hypothermia it is used to induce, what the gut and liver do to it, and what it does without TRPV1 (2026-09-21)","claim_ids":["aee7800b-04f9-5cd0-b419-2a9deadf25b9"]}]}],"corrections":[],"research":null}