BackgroundTherapeutic hypothermia, a novel method of neuroprotection from hypoxia, is complicated by cold‐defensive shivering and tachycardia. These responses are controlled primarily by peripheral cold and warm receptors in the skin through distinct afferent neural pathways. The TRPM8 ion channel is a molecular cold sensor of the primary cold‐sensitive neurons, while TRPV1 is a warm and capsaicin receptor within the afferent pathway for skin warming. Our objective was to test if pharmacological modulation of TRPV1 and TRPM8 can suppress cold‐induced shivering and tachycardia in a whole‐animal mouse model.MethodsConscious freely moving mice were injected with the TRPM8 antagonist “compound 5” or TRPV1 agonist dihydrocapsaicin and exposed to cold (10°C). Shivering was measured by a novel method based on electromyography and heart rate was determined by ECG. Core temperature (abdominal) was measured by implanted wireless transponders.ResultsTRPM8 inhibition had no effect on shivering and tachycardia (also confirmed using TRPM8 KO mice). TRPV1 activation led to substantial suppression of the shivering and tachycardic responses to cold, as well as to a large drop in core temperature. Combined treatment led to near complete inhibition of shivering.ConclusionTRPV1 activation, but not TRPM8 inhibition, reversibly suppresses cold‐induced shivering and tachycardia. Supported by NINDS NS077413.