AMG0347

This study aimed at determining the thermoregulatory phenotype of mice lacking transient receptor potential vanilloid-1 (TRPV1) channels. We usedTrpv1knockout (KO) mice and their genetically unaltered littermates to study diurnal variations in deep body temperature (Tb) and thermoeffector activities under basal conditions, as well as thermoregulatory responses to severe heat and cold. Only subtle alterations were found in the basalTbofTrpv1KO mice or in theirTbresponses to thermal challenges. The main thermoregulatory abnormality ofTrpv1KO mice was a different pattern of thermoeffectors used to regulateTb. On the autonomic side,Trpv1KO mice were hypometabolic (had a lower oxygen consumption) and hypervasoconstricted (had a lower tail skin temperature). In agreement with the enhanced skin vasoconstriction,Trpv1KO mice had a higher thermoneutral zone. On the behavioral side,Trpv1KO mice preferred a lower ambient temperature and expressed a higher locomotor activity. Experiments with pharmacological TRPV1 agonists (resiniferatoxin and anandamide) and a TRPV1 antagonist (AMG0347) confirmed that TRPV1 channels located outside the brain tonically inhibit locomotor activity. With age (observed for up to 14 months), the body mass ofTrpv1KO mice exceeded that of controls, sometimes approaching 60 g. In summary,Trpv1KO mice possess a distinct thermoregulatory phenotype, which is coupled with a predisposition to age-associated overweight and includes hypometabolism, enhanced skin vasoconstriction, decreased thermopreferendum, and hyperkinesis. The latter may be one of the primary deficiencies inTrpv1KO mice. We propose that TRPV1-mediated signals from the periphery tonically suppress the general locomotor activity.