Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization. Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terpenes found in Cannabis for activity at TRPV1. We used inducible expression of TRPV1 to examine TRPV1-dependency of terpene-induced calcium flux responses. Terpenes contribute differentially to calcium fluxes via TRPV1 induced by Cannabis-mimetic cannabinoid/terpenoid mixtures. Myrcene dominates the TRPV1-mediated calcium responses seen with terpenoid mixtures. Myrcene-induced calcium influx is inhibited by the TRPV1 inhibitor capsazepine and Myrcene elicits TRPV1 currents in the whole-cell patch-clamp configuration. TRPV1 currents are highly sensitive to internal calcium. When Myrcene currents are evoked, they are distinct from capsaicin responses on the basis of I_max and their lack of shift to a pore-dilated state. Myrcene pre-application and residency at TRPV1 appears to negatively impact subsequent responses to TRPV1 ligands such as Cannabidiol, indicating allosteric modulation and possible competition by Myrcene. Molecular docking studies suggest a non-covalent interaction site for Myrcene in TRPV1 and identifies key residues that form partially overlapping Myrcene and Cannabidiol binding sites. We identify several non-Cannabis plant-derived sources of Myrcene and other compounds targeting nociceptive TRPs using a data mining approach focused on analgesics suggested by non-Western Traditional Medical Systems. These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.

TRPV1 等伤害性瞬时受体电位通道是治疗疼痛的靶标。TRP 通道的拮抗和激动均可通过失活和慢性脱敏来促进镇痛。由于植物来源的大麻素混合物和大麻成分月桂烯已被建议作为疼痛治疗剂，我们筛选了大麻中发现的萜烯的 TRPV1 活性。我们使用 TRPV1 的诱导表达来检查萜烯诱导的钙流反应的 TRPV1 依赖性。萜烯通过由大麻模拟大麻素/萜类混合物诱导的TRPV1对钙通量的贡献不同。月桂烯主导了萜类混合物中 TRPV1 介导的钙反应。月桂烯诱导的钙内流被 TRPV1 抑制剂辣椒西平抑制，并且月桂烯在全细胞膜片钳配置中引发 TRPV1 电流。TRPV1 电流对内部钙高度敏感。当月桂烯电流被诱发时，它们与基于 I _max的辣椒素反应不同，并且它们没有转变为孔扩张状态。月桂烯在 TRPV1 的预申请和驻留似乎会对随后对 TRPV1 配体（如大麻二酚）的反应产生负面影响，表明月桂烯的变构调节和可能的竞争。分子对接研究表明 TRPV1 中存在月桂烯非共价相互作用位点，并鉴定了形成部分重叠月桂烯和大麻二酚结合位点的关键残基。我们使用非西方传统医疗系统建议的专注于镇痛药的数据挖掘方法，确定了几种非大麻植物来源的月桂烯和其他针对伤害性 TRP 的化合物。这些数据将 TRPV1 确立为月桂烯的靶标，并表明含有月桂烯的镇痛制剂具有治疗潜力。