The cold-defence response that opposes induced cooling

What acts on it

1. 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.

   Dihydrocapsaicin → The cold-defence response that opposes induced cooling source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

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   experimental_model

   Dose-ranging subcutaneous administration in rats with repeated dosing, antinociception testing and regional substance P measurement

   exposure

   Dihydrocapsaicin 0.5 to 10 mg/kg subcutaneously, single and repeated, against capsaicin

   limitations

   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.

   nutrient_topic

   Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. · Dihydrocapsaicin

   organism

   Rat

   plain_language

   Give it repeatedly and the cooling effect fades, and the fading carries across to capsaicin.

   primary_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

   tissue_or_cell_type

   Whole body, dorsal root ganglia and spinal cord

   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) · lines 192–203

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dose-ranging subcutaneous administration in rats with repeated dosing, antinociception testing and regional substance P measurement · source_derived_draft · unverified_draft

   ### dhc-early-desensitisation 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. Condition category: normal nutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. plain_language: Give it repeatedly and the cooling effect fades, and the fading carries across to capsaicin. organism: Rat tissue_or_cell_type: Whole body, dorsal root ganglia and spinal cord experimental_model: Dose-ranging subcutaneous administration in rats with repeated dosing, antinociception testing and regional substance P measurement limitations: 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. exposure: Dihydrocapsaicin 0.5 to 10 mg/kg subcutaneously, single and repeated, against capsaicin evidence_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"} [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

   Complete structured claim and evidence

2. In conscious mice exposed to cooling at 10 degrees, TRPV1 activation by dihydrocapsaicin substantially suppressed total electromyographic muscle activity from 25.6 to 5.1 volt-seconds per minute, abolished the tachycardic response with heart rate change falling from 204 to 3 beats per minute, and produced a profound drop in core temperature from -2.2 to -8.9 degrees.

   Dihydrocapsaicin → The cold-defence response that opposes induced cooling source_derived_draftungraded
   Experimental context and source evidence

   evidence_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"}

   experimental_model

   Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters

   exposure

   TRPV1 agonist dihydrocapsaicin or TRPM8 inhibitor compound 5, with TRPM8 knockout mice as a control

   limitations

   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.

   nutrient_topic

   Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. · Dihydrocapsaicin

   organism

   Mouse

   plain_language

   It switches off the shivering and racing heart that normally fight off cooling, so the temperature falls much further.

   primary_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

   tissue_or_cell_type

   Back muscle, heart and core

   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) · lines 244–255

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters · source_derived_draft · unverified_draft

   ### dhc-suppresses-cold-defence In conscious mice exposed to cooling at 10 degrees, TRPV1 activation by dihydrocapsaicin substantially suppressed total electromyographic muscle activity from 25.6 to 5.1 volt-seconds per minute, abolished the tachycardic response with heart rate change falling from 204 to 3 beats per minute, and produced a profound drop in core temperature from -2.2 to -8.9 degrees. Condition category: normal nutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. plain_language: It switches off the shivering and racing heart that normally fight off cooling, so the temperature falls much further. organism: Mouse tissue_or_cell_type: Back muscle, heart and core experimental_model: Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters limitations: 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. exposure: TRPV1 agonist dihydrocapsaicin or TRPM8 inhibitor compound 5, with TRPM8 knockout mice as a control evidence_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"} [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

   Complete structured claim and evidence

3. 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.

   Experimental TRPM8 knockout mouse genotype → The cold-defence response that opposes induced cooling source_derived_draftungraded
   Experimental context and source evidence

   evidence_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"}

   experimental_model

   Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters

   exposure

   TRPV1 agonist dihydrocapsaicin or TRPM8 inhibitor compound 5, with TRPM8 knockout mice as a control

   limitations

   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.

   nutrient_topic

   Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. · Dihydrocapsaicin

   organism

   Mouse

   plain_language

   Deleting the cold receptor changed nothing about the body’s answer to cold.

   primary_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

   tissue_or_cell_type

   Back muscle, heart and core

   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) · lines 257–268

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters · source_derived_draft · unverified_draft

   ### dhc-trpm8-ablation-does-nothing 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. Condition category: normal nutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. plain_language: Deleting the cold receptor changed nothing about the body’s answer to cold. organism: Mouse tissue_or_cell_type: Back muscle, heart and core experimental_model: Conscious mice exposed to 10 degree cooling with implanted electromyography electrodes, electrocardiography and abdominal temperature transmitters limitations: 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. exposure: TRPV1 agonist dihydrocapsaicin or TRPM8 inhibitor compound 5, with TRPM8 knockout mice as a control evidence_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"} [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

   Complete structured claim and evidence