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Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans

Narender R Gavva1, James J S Treanor, Andras Garami

  • 1Department of Neuroscience, MS 29-2-B, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. ngavva@amgen.com

Pain
|March 14, 2008
PubMed

Insights

TRPV1 antagonists, like AMG 517, can cause significant hyperthermia. This side effect, influenced by individual susceptibility, limits their use for pain management and highlights TRPV1

Area of Science:

  • Pharmacology
  • Neuroscience
  • Pain Management

Background:

  • The vanilloid receptor TRPV1 is a target for treating pain in inflammatory diseases and cancer.
  • TRPV1 antagonists are being evaluated for therapeutic potential.

Purpose of the Study:

  • To investigate the safety and side effects of AMG 517, a selective TRPV1 antagonist, in human clinical trials.
  • To explore the mechanisms underlying AMG 517-induced hyperthermia.

Main Methods:

  • Phase I clinical trials were conducted with AMG 517.
  • Hyperthermia was assessed in relation to plasma concentration and repeated dosing.
  • Mechanisms of hyperthermia were studied in rat models.

Main Results:

  • AMG 517 induced dose-dependent and reversible hyperthermia in humans.
  • Hyperthermia was attenuated with repeated dosing but severe after acute pain stimulus (molar extraction).
  • In rats, AMG 517 caused hyperthermia via tail skin vasoconstriction and increased thermogenesis.

Conclusions:

  • TRPV1 antagonists like AMG 517 are not suitable for standalone systemic use due to hyperthermia.
  • Individual susceptibility significantly impacts the severity of hyperthermia.
  • TRPV1 plays a critical role in regulating human body temperature.

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