Role of endogenous vanilloids and cannabinoids in pain

描述(申请人提供)：对身体产生的促进和抗伤害感受性分子的研究可能会为改进疼痛的治疗产生重要的靶点。最近一个有希望的研究途径是阐明一类被称为脂肪酸酰胺的脂质信号分子的生物学效应。拟议的实验集中在N-酰基多巴胺的表征上，N-酰基多巴胺是一种新的脂肪酸酰胺类化合物，可以作为香草素和/或大麻受体的信号配体。由于大麻素受体的激活通常抑制疼痛，而香草素受体的激活(如辣椒素)通常增强对疼痛的敏感性，N-酰基多巴胺可能内源性地起到促进或抑制疼痛的作用。我们假设这些分子的作用取决于它们形成的位置和细胞环境的状态。因此，我们计划研究这些化合物在神经系统内不同部位的存在，以及各种生理和病理生理条件(如炎症)对它们的形成和生物活性的影响。除了检查大麻素和香草素的机制外，我们还计划检查我们在体内观察到的NADA的氧化代谢物。该提案旨在阐明内源性N-酰基多巴胺及其氧化代谢物的生物学和功能，以加强我们对这类新兴分子的理解，这类分子可能对疼痛的感知和调节具有重要意义。更好地了解这一系统可能会为旨在治疗疼痛和/或炎症的药物开发产生新的靶点。

DESCRIPTION (provided by applicant): The study of pro- and anti-nociceptive molecules produced by the body may yield important targets for improved treatments of pain. A recent and promising avenue of research has been the elucidation of the biological effects of a family of lipid signalling molecules referred to as fatty acid amides. The proposed experiments focus on the characterization of N-acyldopamines, a novel group of fatty acid amides that may serve as signalling ligands for the vanilloid and/or cannabinoid receptors. Since activation of cannabinoid receptors typically suppresses pain, while activation of vanilloid receptors (e.g. by capsaicin) typically heightens sensitivity to pain, N-acyldopamines may serve endogenously to facilitate or dampen pain. We hypothesize that the actions of these molecules depend on the locations at which they are formed and the state of the cellular environment. Hence, we plan to investigate the occurrence of these compounds at various sites within the nervous system and the effect of various physiological and pathophysiological conditions such as inflammation on their formation and bioactivity. In addition to examining cannabinoid and vanilloid mechanisms, we plan to examine oxygenated metabolites of NADA that we observed in vivo. The proposal aims to elucidate the biology and function of endogenous N-acyldopamines and their oxygenated metabolites in order to enhance our understanding of this emerging class of molecules, which may be important to the perception and modulation of pain. A better understanding of this system may yield novel targets for drug development aimed at treating pain and/or inflammation.