title: Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition.
abstract: Mild decrease of core temperature (32-34°C), also known as therapeutic hypothermia, is a highly effective strategy of neuroprotection from ischemia and holds significant promise in the treatment of stroke. However, induction of hypothermia in conscious stroke patients is complicated by cold-defensive responses, such as shivering and tachycardia. Although multiple thermoregulatory responses may be altered by modulators of thermosensitive ion channels, TRPM8 (transient receptor potential melastatin 8) and TRPV1 (TRP vanilloid 1), it is unknown whether these agents affect cold-induced shivering and tachycardia. The current study aimed to determine the effects of TRPM8 inhibition and TRPV1 activation on the shivering and tachycardic responses to external cooling. Conscious mice were treated with TRPM8 inhibitor compound 5 or TRPV1 agonist dihydrocapsaicin (DHC) and exposed to cooling at 10°C. Shivering was measured by electromyography using implanted electrodes in back muscles, tachycardic response by electrocardiography, and core temperature by wireless transmitters in the abdominal cavity. The role of TRPM8 was further determined using TRPM8 KO mice. TRPM8 ablation had no effect on total electromyographic muscle activity (vehicle: 24.0 ± 1.8; compound 5: 23.8 ± 2.0; TRPM8 KO: 19.7 ± 1.9 V·s/min), tachycardia (ΔHR = 124 ± 31; 121 ± 13; 121 ± 31 beats/min) and drop in core temperature (-3.6 ± 0.1; -3.4 ± 0.4; -3.6 ± 0.5°C) during cold exposure. TRPV1 activation substantially suppressed muscle activity (vehicle: 25.6 ± 3.0 vs. DHC: 5.1 ± 2.0 V·s/min), tachycardia (ΔHR = 204 ± 25 vs. 3 ± 35 beats/min) and produced a profound drop in core temperature (-2.2 ± 0.6 vs. -8.9 ± 0.6°C). In conclusion, external cooling-induced shivering and tachycardia are suppressed by TRPV1 activation, but not by TRPM8 inhibition. This suggests that TRPV1 agonists may be combined with external physical cooling to achieve more rapid and effective hypothermia.
authors.affiliation: Department of Molecular Physiology and Biophysics Graduate Program, Cardiovascular Sciences Track, Baylor College of Medicine, Houston, Texas;
authors.forename: Viktor V
authors.initials: VV
authors.lastname: Feketa
authors.forename: Adithya
authors.initials: A
authors.lastname: Balasubramanian
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Flores
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Sean P
authors.initials: SP
authors.lastname: Marrelli
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D007036:Hypothermia, Induced / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012768:Shivering / Q000187:drug effects*; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists* / Q000378:metabolism; D013610:Tachycardia / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D001562:Benzimidazoles; D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C498947:Trpm8 protein, rat; D002211:Capsaicin; C012906:dihydrocapsaicin
keywords: dihydrocapsaicin; electromyography; pharmacological hypothermia; physical cooling; shivering; therapeutic hypothermia; transient receptor potential