Answering the burning question of how transient receptor potential vanilloid-1 channel antagonists cause unwanted hyperthermia.

The treatment of chronic pain with new therapies that lack the side effects of existing analgesics is one of medicine's great unmet needs. Toward this goal, antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel have shown some promise. However, the development of these compounds has been hindered by an unpleasant on-target hyperthermic side effect. With compelling evidence, the accompanying critical review by Romanovsky et al. (p. 228) regarding TRPV1 takes a position on the sites of action of TRPV1 agonists and antagonists on the thermoregulatory system that controls this side effect. From this comes insight on potential ways to overcome the unwanted hyperthermic action of TRPV1 antagonists.