Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Str., Moscow 117997, Russia.
Mar Drugs. 2013 Dec 16;11(12):5100-15. doi: 10.3390/md11125100.
Transient receptor potential vanilloid 1 receptors (TRPV1) play a significant physiological role. The study of novel TRPV1 agonists and antagonists is essential. Here, we report on the characterization of polypeptide antagonists of TRPV1 based on in vitro and in vivo experiments. We evaluated the ability of APHC1 and APHC3 to inhibit TRPV1 using the whole-cell patch clamp approach and single cell Ca2+ imaging. In vivo tests were performed to assess the biological effects of APHC1 and APHC3 on temperature sensation, inflammation and core body temperature. In the electrophysiological study, both polypeptides partially blocked the capsaicin-induced response of TRPV1, but only APHC3 inhibited acid-induced (pH 5.5) activation of the receptor. APHC1 and APHC3 showed significant antinociceptive and analgesic activity in vivo at reasonable doses (0.01-0.1 mg/kg) and did not cause hyperthermia. Intravenous administration of these polypeptides prolonged hot-plate latency, blocked capsaicin- and formalin-induced behavior, reversed CFA-induced hyperalgesia and produced hypothermia. Notably, APHC3's ability to inhibit the low pH-induced activation of TRPV1 resulted in a reduced behavioural response in the acetic acid-induced writhing test, whereas APHC1 was much less effective. The polypeptides APHC1 and APHC3 could be referred to as a new class of TRPV1 modulators that produce a significant analgesic effect without hyperthermia.
瞬时受体电位香草酸 1 型受体（TRPV1）在生理上具有重要作用。研究新型 TRPV1 激动剂和拮抗剂至关重要。在此，我们报告了基于体外和体内实验的 TRPV1 多肽拮抗剂的特征。我们使用全细胞膜片钳技术和单细胞 Ca2+成像技术评估了 APHC1 和 APHC3 抑制 TRPV1 的能力。进行了体内测试以评估 APHC1 和 APHC3 对温度感觉、炎症和核心体温的生物学效应。在电生理研究中，两种多肽均部分阻断了 TRPV1 对辣椒素的反应，但只有 APHC3 抑制了酸诱导（pH 5.5）对受体的激活。在合理剂量（0.01-0.1mg/kg）下，APHC1 和 APHC3 在体内表现出显著的镇痛和止痛活性，且不会引起体温过高。这些多肽的静脉给药延长了热板潜伏期，阻断了辣椒素和福尔马林引起的行为，逆转了 CFA 引起的痛觉过敏，并导致体温过低。值得注意的是，APHC3 抑制低 pH 诱导的 TRPV1 激活的能力导致在醋酸诱导的扭体试验中行为反应减少，而 APHC1 的效果则差得多。多肽 APHC1 和 APHC3 可被称为一类新的 TRPV1 调节剂，它们在不引起体温过高的情况下产生显著的镇痛作用。
