Cannabidiol and terpenoid interactions in amygdalar regulation of pain states

大麻二酚和萜类化合物在杏仁核疼痛状态调节中的相互作用

基本信息

批准号：
10613537
负责人：
Benjamin Land
金额：
$ 44.6万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613537
关键词：
Absence of pain sensation Acute Acute Pain Acute inflammatory pain Affect American Amygdaloid structure Analgesics Behavior Behavioral Benefits and Risks Beta-caryophyllene Biochemical Biochemical Pathway Biological Assay Brain CNR1 gene CNR2 gene Calcium Cannabidiol Cannabinoids Cannabis Cell Nucleus Cells Cellular Assay Chemicals Chronic Chronic inflammatory pain Clustered Regularly Interspaced Short Palindromic Repeats Consumption Data Dose Euphoria Experimental Models G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gelatin Generations Glutamates Image In Vitro Inflammatory Injections Ion Channel Knock-out Ligation MAPK8 gene Measures Mediating Medical Marijuana Mitogen-Activated Protein Kinases Modeling Molecular Morphine Mus N-terminal Neurons Neuropathy Nociception Non-Steroidal Anti-Inflammatory Agents Opioid Oral Pain Pain management Pathway interactions Persons Pharmaceutical Preparations Pharmacodynamics Pharmacology Phosphotransferases Physical Dependence Physiological Plants Population Property Proxy Public Health Reactive Oxygen Species Regulation Reporting Research Personnel Rewards Risk Role Self Administration Signal Pathway Signal Transduction Site Substance abuse problem System Terpenes Testing Therapeutic Time Tissues United States United States National Institutes of Health abuse liability addiction antagonist antinociception awake cannabinoid receptor central pain chronic neuropathic pain chronic pain chronic pain management combat conditioned place preference efficacy evaluation efficacy testing experimental study improved in vivo inflammatory pain insight knockout animal lens linalool neural opioid epidemic opioid use pain inhibition pain model pain reduction pain relief pain score painful neuropathy pharmacologic phytocannabinoid preclinical study prevent receptor recruit response sciatic nerve sciatic nerve injury sensor side effect standard care

项目摘要

PROJECT SUMMARY Chronic pain affects up to one third of the United States population, and the reliance on opioids to treat chronic pain has contributed substantially to the opioid epidemic. Developing alternative pain therapies is critical to reducing the use of opioids, and the phyto-cannabinoid cannabidiol (CBD) is a promising candidate. We have shown that CBD has the ability to reduce chronic neuropathic pain-like responses in mice over 3 weeks. Terpenoids (eg beta-caryophyllene), also found in the cannabis plant, are a potential second class of pharmacologically active compounds in cannabis with possible analgesic benefits, although their pharmacodynamic properties in vitro and in vivo are poorly understood. Likewise, there is an incomplete understanding of how CBD and terpenoids produce anti-nociception, by themselves or combined (“entourage”), and their supraspinal neuropharmacological mechanisms of “pain control” remain unknown. The proposed experiments will first test whether specific combinations of CBD and terpenoids can produce short-term inflammatory and long-term neuropathic antinociception without tolerance. We will then establish the action of CBD and terpenoids in a critical brain nucleus for pain, the basolateral amygdala. Finally, we will determine the pharmacological and biochemical signaling profiles of CBD and terpenoids in vitro and in vivo. In Aim 1, we will use mixtures of CBD and terpenoids, investigator administered as well as in our gelatin self-administration model, and measure both consumption and pain scores after partial sciatic nerve ligation to determine if CBD and/or terpenoids provide analgesic benefit over protracted periods of pain. We will also verify that these mixtures are not inherently rewarding, which is critical for substance abuse liability. In Aim 2, we will test whether the amygdala is a critical brain circuit site for CBD/terpenoid analgesic action using single cell calcium imaging of amygdalar neurons during pain states, in parallel with local injections of CBD and terpenoids into the amygdala to produce analgesia. Further, we will knock out cannabinoid receptors and other putative sites of CBD/terpenoid action within the BLA to establish necessity of each in producing behavioral and physiological responses. In Aim 3, we will use in vitro and in vivo systems to determine the important biochemical features of CBD and terpenoid action at their putative receptor targets. We will measure cellular signaling activity via dynamic mass redistribution (DMR), MAP Kinase signaling, and the generation of reactive oxygen species. These aims will inform public health about the benefits and risks of long-term cannabidiol/terpenoid usage, as well as providing crucial mechanistic insight that will help develop and understand whether tailored medicinal cannabis approaches for chronic pain can be harnessed for therapeutic benefit.

项目概要慢性疼痛影响着多达三分之一的美国人口，并且依赖阿片类药物来治疗慢性疼痛疼痛在很大程度上导致了阿片类药物的流行，开发替代性疼痛疗法对于缓解疼痛至关重要。减少阿片类药物的使用，而植物大麻二酚（CBD）是一个有前途的候选药物。研究表明，CBD 能够在 3 周内减少小鼠的慢性神经性疼痛样反应。萜类化合物（例如 β-石竹烯）也存在于大麻植物中，是潜在的第二类化合物大麻中的药理活性化合物可能具有镇痛作用，尽管它们同样，对体外和体内的药效学特性也知之甚少。了解 CBD 和萜类化合物如何单独或组合（“随行人员”）产生抗伤害作用，其“疼痛控制”的脊髓上神经药理学机制仍不清楚。实验将首先测试 CBD 和萜类化合物的特定组合是否可以产生短期效果然后我们将建立无耐受性的炎症和长期神经性抗伤害作用。 CBD 和萜类化合物在疼痛的关键脑核——基底外侧杏仁核中的作用。确定 CBD 和萜类化合物的体外和体内药理学和生化信号传导谱在目标 1 中，我们将使用 CBD 和萜类化合物的混合物，以及在我们的明胶中使用。自我给药模型，并测量部分坐骨神经结扎后的消耗和疼痛评分确定 CBD 和/或萜类化合物是否在长时间的疼痛中提供镇痛效果。这些混合物本身并不有益，这对于药物滥用责任至关重要，在目标 2 中，我们将这样做。使用单细胞测试杏仁核是否是 CBD/萜类镇痛作用的关键脑回路部位疼痛状态下杏仁核神经元的钙成像，同时局部注射 CBD 和萜类化合物此外，我们将敲除大麻素受体和其他假定的受体。 BLA 内 CBD/萜类化合物作用位点，以确定每个位点在产生行为和在目标 3 中，我们将使用体外和体内系统来确定重要的生化反应。我们将测量 CBD 和萜类化合物在其假定受体靶点上的作用特征。通过动态质量再分配 (DMR)、MAP 激酶信号传导和活性氧的产生。这些目标将使公众健康了解长期使用大麻二酚/萜类化合物的益处和风险，因为以及提供重要的机制见解，这将有助于开发和理解是否定制药物大麻治疗慢性疼痛的方法可以用于治疗以获得益处。