Agonists of the transient receptor potential vanilloid type 1 (TRPV1), such as capsaicin, cause pain and a drop in body temperature (hypothermia). Conversely, antagonists of TRPV1 block pain behaviors in rodent models of inflammation, osteoarthritis and cancer. Efforts that evaluate TRPV1 antagonists in on-target challenge models have uncovered that TRPV1 blockade elicits an increase in body temperature (hyperthermia) from rodents to primates, revealing the intimate relationship between the role of TRPV1 in pain and body-temperature maintenance. This evolutionarily conserved function of TRPV1 in body-temperature maintenance became a hurdle for clinical development of one antagonist, AMG 517. However, several other TRPV1 antagonists are currently being evaluated in the clinic and soon-to-be-published results should shed light on the potential of managing antagonist-induced hyperthermia while developing them as therapeutics.
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