Turning down the body heat: A novel mechanism for TRPV1 antagonist-induced hyperthermia

While effective analgesics, TRPV1 antagonists can dangerously alter thermoregulation. In this issue of Neuron, Huang et al. 1 Huang Y.-Z. Ma J.-X. Bian Y.-J. Bai Q.-R. Gao Y.-H. Di S.-K. Lei Y.-T. Yang H. Yang X.-N. Shao C.-Y. et al. TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception. Neuron. 2024; 112: 1815-1831.e4https://doi.org/10.1016/j.neuron.2024.02.016 Abstract Full Text Full Text PDF Scopus (2) Google Scholar demonstrate that interaction with the S4-S5 linker of TRPV1 determines whether an antagonist affects core body temperature, with promising implications for analgesic development. While effective analgesics, TRPV1 antagonists can dangerously alter thermoregulation. In this issue of Neuron, Huang et al. 1 Huang Y.-Z. Ma J.-X. Bian Y.-J. Bai Q.-R. Gao Y.-H. Di S.-K. Lei Y.-T. Yang H. Yang X.-N. Shao C.-Y. et al. TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception. Neuron. 2024; 112: 1815-1831.e4https://doi.org/10.1016/j.neuron.2024.02.016 Abstract Full Text Full Text PDF Scopus (2) Google Scholar demonstrate that interaction with the S4-S5 linker of TRPV1 determines whether an antagonist affects core body temperature, with promising implications for analgesic development. TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociceptionHuang et al.NeuronMarch 15, 2024In BriefDevelopment of analgesics targeting TRPV1 receptors has been hampered by undesirable hypo- or hyperthermic effects induced by TRPV1 agonists/antagonists. Huang et al. suggest that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, which may be selectively targeted for developing non-opioid analgesics without the confounding CBT alterations. Full-Text PDF