2. Academic Validation
  3. TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception

TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception

  • Neuron. 2024 Jun 5;112(11):1815-1831.e4. doi: 10.1016/j.neuron.2024.02.016.
Yi-Zhe Huang 1,  Jing-Xian Ma 1,  Yu-Jing Bian 1,  Qin-Ru Bai 1,  Yu-Hao Gao 1,  Shu-Ke Di 1,  Yun-Tao Lei 1,  Hui Yang 2,  Xiao-Na Yang 3,  Chang-Yan Shao 1,  Wen-Hui Wang 1,  Peng Cao 4,  Chang-Zhu Li 5,  Michael X Zhu 6,  Meng-Yang Sun 7,  Ye Yu 8
Affiliations

Affiliations

  • 1 Schools of Basic Medicine and Clinical Pharmacy and Traditional Chinese Pharmacy, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Tea Research Institute, Hunan Academy of Agricultural Sciences, Changsha 410125, Hunan, China.
  • 3 College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China.
  • 4 Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5 State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Changsha 410004, Hunan, China.
  • 6 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • 7 Schools of Basic Medicine and Clinical Pharmacy and Traditional Chinese Pharmacy, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: mengyangsun@cpu.edu.cn.
  • 8 Schools of Basic Medicine and Clinical Pharmacy and Traditional Chinese Pharmacy, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yuye@cpu.edu.cn.
PMID: 38492574 DOI: 10.1016/j.neuron.2024.02.016
Abstract

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

Keywords

S4-S5 linker domain; TRP-box domain; TRPV1 analgesics; biased allosteric mechanism; core body temperature; hyperthermia; nociception.

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