{"id":"ac72e08f-254b-59f0-9108-801dd7cfe767","stable_key":"c953cca8-774f-596d-b27a-f13c2c0b5fce:dhc-trpm8-ablation-does-nothing","predicate":"preserves_measured_pool","statement":"TRPM8 ablation had no effect on total electromyographic muscle activity, on tachycardia, or on the drop in core temperature during cold exposure, with vehicle, compound 5 and TRPM8 knockout values closely similar across all three measures.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"78167466-0961-5590-b8da-22b9d4b4c473","mechanism_event_label":"Deleting the cold receptor changed nothing about the body’s answer to cold.","subject":{"id":"8f3eca1a-3d1d-5649-83fb-6f88cbd10f1c","slug":"trpm8-null","display_name":"Experimental TRPM8 knockout mouse genotype","entity_type_key":"protein_state"},"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":"78167466-0961-5590-b8da-22b9d4b4c473","stable_key":"c953cca8-774f-596d-b27a-f13c2c0b5fce:dhc-trpm8-ablation-does-nothing-event","event_type":"observed_intervention","label":"Deleting the cold receptor changed nothing about the body’s answer to cold.","description":"TRPM8 ablation had no effect on total electromyographic muscle activity, on tachycardia, or on the drop in core temperature during cold exposure, with vehicle, compound 5 and TRPM8 knockout values closely similar across all three measures.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"8774e0b8-ac63-5cdf-b8f7-83365dbbb5c4","slug":"trpm8","display_name":"Transient receptor potential melastatin 8 / TRPM8 cold and menthol receptor","entity_type_key":"protein"},"role":"deleted_channel","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"5d0fd0d4-0780-559b-8be7-5ca205f61447","slug":"trpm8-inhibitor-compound-5","display_name":"The TRPM8 inhibitor referred to as compound 5","entity_type_key":"chemical_species"},"role":"comparator_treatment","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"8f3eca1a-3d1d-5649-83fb-6f88cbd10f1c","slug":"trpm8-null","display_name":"Experimental TRPM8 knockout mouse genotype","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":2,"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":3,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/dihydrocapsaicin-research/24005250.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"e9d99ac4cc7a031474975ac4d7f3bcff0df922dc01047fe94bd51817ef5b3fea\", \"start_char\": 0, \"end_char\": 1963, \"text_sha256\": \"e9d99ac4cc7a031474975ac4d7f3bcff0df922dc01047fe94bd51817ef5b3fea\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"TRPV1 agonist dihydrocapsaicin or TRPM8 inhibitor compound 5, with TRPM8 knockout mice as a control","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"This is the record that explains why the drug is clinically interesting rather than merely cooling: it removes the defence that makes physical cooling intolerable in a conscious patient.","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":"Mouse","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Deleting the cold receptor changed nothing about the body’s answer to cold.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[dhc-p24005250] Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition. (2013). https://pubmed.ncbi.nlm.nih.gov/24005250/ DOI: 10.1152/ajpregu.00296.2013","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Back muscle, heart and core","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"fa4bebcc-4fad-5f5a-b14a-19cac99e2cfa","evidence_kind":"source_excerpt","locator":"Lines 257-268","start_line":257,"end_line":268,"excerpt":"### dhc-trpm8-ablation-does-nothing\nTRPM8 ablation had no effect on total electromyographic muscle activity, on tachycardia, or on the drop in core temperature during cold exposure, with vehicle, compound 5 and TRPM8 knockout values closely similar across all three measures.\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: Deleting the cold receptor changed nothing about the body’s answer to cold.\norganism: Mouse\ntissue_or_cell_type: Back muscle, heart and core\nexperimental_model: Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters\nlimitations: This is the record that explains why the drug is clinically interesting rather than merely cooling: it removes the defence that makes physical cooling intolerable in a conscious patient.\nexposure: TRPV1 agonist dihydrocapsaicin or TRPM8 inhibitor compound 5, with TRPM8 knockout mice as a control\nevidence_span: {\"source_cache\": \"artifacts/dihydrocapsaicin-research/24005250.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"e9d99ac4cc7a031474975ac4d7f3bcff0df922dc01047fe94bd51817ef5b3fea\", \"start_char\": 0, \"end_char\": 1963, \"text_sha256\": \"e9d99ac4cc7a031474975ac4d7f3bcff0df922dc01047fe94bd51817ef5b3fea\"}\n[dhc-p24005250] Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition. (2013). https://pubmed.ncbi.nlm.nih.gov/24005250/ DOI: 10.1152/ajpregu.00296.2013","model_system":"Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [dhc-p24005250] Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition. (2013). https://pubmed.ncbi.nlm.nih.gov/24005250/ DOI: 10.1152/ajpregu.00296.2013","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":"ab9c0539-8c07-57f8-86e2-4785f9507760","title":"Does blocking TRPM8 change the response to cold, or not?","kind":"contradiction","status":"open","why":"Genetic ablation of TRPM8 had no effect on shivering, on tachycardia, or on the fall in core temperature during cold exposure in mice. A pharmacological TRPM8 inhibitor in the same laboratory augmented the drop in core temperature during cold exposure and amplified dihydrocapsaicin-induced hypothermia when the two were combined. The endpoints are not identical, one study measured the defence responses and the other the resulting temperature, and a knockout animal has had a lifetime to compensate where an acutely dosed animal has not. The inhibitor may also act on something other than TRPM8. The disagreement between the genetic and the pharmacological result is recorded rather than resolved.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 03:40:20","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/ab9c0539-8c07-57f8-86e2-4785f9507760","sides":[{"conflict_id":"ab9c0539-8c07-57f8-86e2-4785f9507760","ordinal":0,"label":"Deleting the cold receptor changed nothing about the body’s answer to cold.","revision_id":"dbdc1ad7-a05a-579d-b2aa-c4348e3efc40","start_line":257,"end_line":268,"quote":"### dhc-trpm8-ablation-does-nothing\nTRPM8 ablation had no effect on total electromyographic muscle activity, on tachycardia, or on the drop in core temperature during cold exposure, with vehicle, compound 5 and TRPM8 knockout values closely similar across all three measures.\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: Deleting the cold receptor changed nothing about the body’s answer to cold.\norganism: Mouse\ntissue_or_cell_type: Back muscle, heart and core\nexperimental_model: Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters\nlimitations: This is the record that explains why the drug is clinically interesting rather than merely cooling: it removes the defence that makes physical cooling intolerable in a conscious patient.\nexposure: TRPV1 agonist dihydrocapsaicin or TRPM8 inhibitor compound 5, with TRPM8 knockout mice as a control\nevidence_span: {\"source_cache\": \"artifacts/dihydrocapsaicin-research/24005250.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"e9d99ac4cc7a031474975ac4d7f3bcff0df922dc01047fe94bd51817ef5b3fea\", \"start_char\": 0, \"end_char\": 1963, \"text_sha256\": \"e9d99ac4cc7a031474975ac4d7f3bcff0df922dc01047fe94bd51817ef5b3fea\"}\n[dhc-p24005250] Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition. (2013). https://pubmed.ncbi.nlm.nih.gov/24005250/ DOI: 10.1152/ajpregu.00296.2013","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":["ac72e08f-254b-59f0-9108-801dd7cfe767"]},{"conflict_id":"ab9c0539-8c07-57f8-86e2-4785f9507760","ordinal":1,"label":"Blocking the cold sensor at the same time makes the cooling go deeper and last longer.","revision_id":"dbdc1ad7-a05a-579d-b2aa-c4348e3efc40","start_line":283,"end_line":294,"quote":"### dhc-trpm8-inhibition-potentiates\nThe TRPM8 inhibitor compound 5 at 20 mg/kg subcutaneously augmented the drop in core temperature during cold exposure at 8 degrees, and when combined with dihydrocapsaicin at 1.25 to 2.5 mg/kg the drop in core temperature was amplified and prolonged, so that activating warm receptors and simultaneously inhibiting cold receptors potentiated the effect.\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: Blocking the cold sensor at the same time makes the cooling go deeper and last longer.\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":["a623dde1-3421-533f-b711-3cd4fa9c9b56"]}]}],"corrections":[],"research":null}