Cannabinoid and terpene regulation of nocioception and peripheral sensitization through ionotropic receptors

大麻衍生疗法有望在疼痛管理中发挥作用。他们的低副作用特征和低 令人上瘾的潜力增加了这一命题的价值，此外，它们已被证明是“不使用阿片类药物”。 然而，目前的医用大麻患者仅限于从合法或非法获得的本地植物混合物 不一致的供应链，容易受到污染问题的影响，以及 配方(植物化学变种)和药效。在过去的几十年里，流行的化学变种已经被挑选出来 不断增加的THC水平，这既是由于THC的精神活动而在医学上不可取的，也可能是 如果THC对于某些适应症来说实际上是可有可无的，那么医学上就没有必要。这些集中的安全性和有效性 问题加强了合理设计治疗方法的必要性，这些治疗方法代表了最低限度的必要和有效的治疗方法。 一组实现止痛所需的化合物。这项临床前提案的总体目标是建立 大麻素(不含THC)、萜类及合理设计的药效和作用机制 大麻素/萜烯混合物可快速翻译用于伤害性感受性临床评估 疼痛和外周敏感症。拟议工作的中心前提是电离性大麻素 受体(瞬时受体电位(Trp)伤害性感受离子通道)是最重要的靶标 大麻中存在的大麻素和萜类化合物的治疗脱敏作用。这项建议在以下方面具有创新性 它把重点放在实际的伤害性感受器上，而不是CB1和CB2GPCR，它排除了 THC，并专注于其他大麻素和萜类化合物，它接受了建立合成混合物的想法， 改进天然植物的有效性和安全性，并排除植物提取物，并提出了一种方法 涉及同时处理伤害性感受和外周敏感化。该项目得到了 初步数据：(A)确定伤害感受性TRPs上CB和TP的不同活性，定义哪些 TRPs是每种化合物的靶标，并识别新的Trp配体，(B)描述复杂的动力学和 CB/TP对色氨酸伤害感受器的脱敏作用，为治疗性脱敏提供了可能性 以及伤害性感受性色氨酸反应的调节；(C)展示了大麻成分对 建立了针对Trp通道的疼痛治疗，以及(D)展示了以下成分的相互作用 复杂的CB/TP混合物，为合理的混合物设计提供信息。提出的具体目标是：目标1.测试 大麻素和萜类对伤害性色氨酸通道的调节。我们假设CB和Tp， 单独或混合，选择性地结扎和脱敏TRPs以促进镇痛。目的2.测定GPCR值 大麻素和萜类化合物镇痛作用中的依赖和关系。我们假设 CB和TP以独立于CB1和CB2 GPCR的多个TRP为靶标，而CB、TP和混合物为靶标 TRPV1将影响阿片类药物的暴露结果。目标3.评估CB和TP的潜力 抑制外周敏化(PS)模型中致敏介质的释放。我们假设 CB和TP单独或混合使用可抑制感觉神经元相关致敏介质的释放 肥大细胞(MC)和嗜碱性粒细胞。这项工作的影响将是为采用或拒绝大麻化合物作为疼痛治疗提供具体的、基于机械的临床前理由，提升该领域 而不是目前对轶事和不完整数据的依赖。在专注于STEM的夏威夷原住民的背景下 为本科院校服务，在本科研究方面有良好的记录，该领域R15项目 将为以本土学生为主的学生群体提供有意义的本科生研究机会 对天然产品和植物衍生药物方法的文化和科学兴趣。

Cannabis-derived therapeutics promise utility in pain management. Their low side effect profile and low addictive potential add value to this proposition, and in addition, they have been shown to be `opioid-sparing'. However, current medical marijuana patients are limited to native plant mixtures obtained licitly or illicitly from an inconsistent supply chain that is subject to issues of contamination and undefined relationships between formulations (plant chemovars) and efficacy. Popular chemovars have been selected over several decades for ever-increasing THC levels, which is both medically undesirable due to the psychoactivity of THC and may be medically unnecessary if THC is actually dispensable for some indications. These central safety and efficacy problems reinforce the need for rational design of therapies that represent the minimal essential and efficacious set of compounds needed to achieve analgesia. The overall goal of this pre-clinical proposal is to establish efficacy and mechanism of action for cannabinoids (excluding THC), terpenes and rationally-designed cannabinoid/terpene mixtures such that they can be rapidly translated for clinical evaluation in nocioceptive pain and peripheral sensitization. The central premise of the proposed work is that ionotropic cannabinoid receptors (Transient Receptor Potential (TRP) nocioceptive ion channels) are the most important targets for therapeutic desensitization by cannabinoids and terpenes present in Cannabis. The proposal is innovative in that it focuses on ionotropic receptors that are actual nocioceptors rather than CB1 and CB2 GPCR, it excludes THC and focuses on other cannabinoids and terpenes, it embraces the idea of building synthetic mixtures that improve upon the natural plant for efficacy and safety and excludes plant extracts, and it proposes an approach to simultaneously addressing both nocioception and peripheral sensitization. The project is supported by preliminary data that: (a) establish differential activity of CB and TP at nocioceptive TRPs, defining which TRPs are targeted by each compound and identifying novel TRP ligands, (b) describe complex kinetics and desensitization of TRP nocioceptors in response to CB/TP, offering the potential for therapeutic desensitization and tuning of nocioceptive TRP responses; (c) demonstrate a Cannabis component improving upon an established pain therapeutic targeting a TRP channel, and (d) demonstrate interactions of components of complex CB/TP mixtures, informing rational mixture design. The proposed Specific Aims are: Aim 1. Test cannabinoid and terpene regulation of nocioceptive TRP channels. We hypothesize that CB and TP, singly or in mixtures, selectively ligate and desensitize TRPs to promote analgesia. Aim 2. Determine GPCR dependencies and relationships in analgesic effects of cannabinoids and terpenes. We hypothesize that CB and TP target multiple TRPs independently of CB1 and CB2 GPCR, and CB, TP and mixtures that target TRPV1 will influence opioid exposure outcomes. Aim 3. Evaluate CB and TP for their potential to suppress sensitizing mediator release in a model of peripheral sensitization (PS). We hypothesize that CB and TP, singly or in mixtures, will inhibit release of sensitizing mediators from sensory neuron associated mast cells (MC) and basophils. The impact of this work will be to provide concrete, mechanistically-based pre-clinical rationales for the adoption or rejection of Cannabis compounds as pain therapies, elevating the field above its current reliance on anecdotal and incomplete data. In the context of a STEM-focused Native Hawaiian serving undergraduate institution with a strong track record in undergraduate research, this AREA R15 project will provide meaningful undergraduate research opportunities to a largely indigenous student body with a keen cultural and scientific interest in natural products and plant-derived medicine approaches.