Background: 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. Modulators of thermosensitive ion channels TRPM8 and TRPV1 alter multiple thermoregulatory responses. However, the regulation of shivering by TRPM8 and TRPV1 is not fully understood. Objective: To determine the effects of TRPM8 inhibition and TRPV1 activation on the shivering and tachycardic responses to external cooling. Methods: Conscious mice were treated with TRPM8 inhibitor "compound 5" or TRPV1 agonist dihydrocapsaicin 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 abdominal cavity. The role of TRPM8 was further determined using TRPM8 KO mice. Results: TRPM8 ablation had no effect on total EMG muscle activity (vehicle: 24.0±1.8; "compound 5": 23.8±2.0; TRPM8 KO: 19.7±1.9 V*s/min), tachycardia (HR=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 EMG muscle activity (vehicle: 25.6±3.0 vs. DHC: 5.1±2.0 V*s/min), tachycardia (HR=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). Conclusions: 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.