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

大麻衍生的治疗方法在疼痛管理中的应用前景。他们的低副作用和低 成瘾潜力增加了这一主张的价值，此外，它们已被证明是“类阿片节省”的。 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，受到污染和不确定的关系之间的问题 制剂（植物化学变体）和功效。几十年来，人们已经选择了流行的化学变体， 不断增加的THC水平，由于THC的精神活性，这在医学上是不期望的，并且可能是 如果THC实际上对某些适应症无效，则在医学上不必要。这些中心的安全性和有效性 这些问题加强了对合理设计治疗的需要，这些治疗代表了最低限度的必要和有效的治疗。 一系列的化合物来达到镇痛效果。本临床前提案的总体目标是建立 大麻素（不包括THC）、萜烯和合理设计的 大麻素/萜烯混合物，使得它们可以快速转化用于伤害感受性疼痛的临床评价。 疼痛和外周致敏。这项工作的中心前提是， 受体（瞬时受体电位（TRP）伤害感受离子通道）是最重要的靶点， 通过大麻中存在的大麻素和萜烯进行治疗性脱敏。该提案具有创新性， 它关注的是离子型受体，而不是CB 1和CB 2 GPCR，它排除了 THC并专注于其他大麻素和萜烯，它拥抱了构建合成混合物的想法， 改进天然植物的功效和安全性，排除植物提取物，并提出了一种方法 同时解决伤害感受和外周敏化。该项目得到了 初步数据：（a）建立CB和TP在伤害感受性TRP上的差异活性， TRP被每种化合物靶向，并鉴定新的TRP配体，（B）描述了复杂的动力学， TRP伤害感受器对CB/TP的脱敏反应，为治疗性脱敏提供了可能性 和调节伤害感受性TRP反应;（c）证明大麻成分改善了 建立的靶向TRP通道的疼痛治疗剂，和（d）证明 复杂的CB/TP混合物，为合理的混合物设计提供信息。建议的具体目标是：目标1。测试 大麻素和萜烯对伤害感受TRP通道的调节。我们假设CB和TP， 单独或以混合物形式，选择性地连接和脱敏TRP以促进镇痛。目标二。测定GPCR 大麻素和萜类的镇痛作用的依赖性和关系。我们假设 CB和TP靶向多种TRP，而不依赖于CB 1和CB 2 GPCR，CB、TP和靶向 TRPV 1将影响阿片类药物暴露结果。目标3.评估CB和TP的潜力， 抑制外周致敏（PS）模型中致敏介质的释放。我们假设 CB和TP，单独或混合，将抑制从感觉神经元释放敏化介质， 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疗法提供具体的，基于机械的临床前依据， 而不是目前依赖于传闻和不完整的数据。在一个以STEM为重点的夏威夷原住民的背景下， 服务于本科院校，在本科研究方面有着良好的记录，这个区域R15项目 将提供有意义的本科生研究机会，主要是土著学生团体与敏锐的 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.