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.

中文翻译：

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TRPV1 镇痛药通过偏向变构机制扰乱核心体温，该机制涉及与伤害感受不同的构象


开发用于疼痛管理的瞬时受体电位香草酸 1 （TRPV1） 药物的努力受到 TRPV1 激动剂/拮抗剂引起的有害低体温或体温过高的阻碍。在这里，我们比较了四种拮抗剂对 Trpv1+/+、Trpv1-/- 和 Trpv1T634A/T634A 中 TRPV1 多峰门控和核心体温 （CBT） 的影响。对质子门控或给药途径、毛发覆盖、CBT 节律波动或炎症的影响均未对 TRPV1 药物对 CBT 的不同作用产生任何影响。我们确定暴露于 TRPV1 香草囊袋的 S4-S5 接头区域对于与某些 TRPV1 拮抗剂相关的热疗至关重要。PSFL2874 是我们发现的一种 TRPV1 拮抗剂，可有效对抗炎症性疼痛，但与 S4-S5 接头结合不诱导 CBT 变化。这些发现表明 TRPV1 与伤害感受和 CBT 调节耦合存在偏倚变构机制，为在不影响 CBT 的情况下开发非阿片类镇痛药开辟了途径。