Role of endogenous vanilloids and cannabinoids in pain

描述（由申请人提供）：对身体产生的促伤害感受分子和抗伤害感受分子的研究可能会产生改善疼痛治疗的重要靶点。最近和有前途的研究途径一直是阐明的一个家庭的脂质信号分子称为脂肪酸酰胺的生物学效应。拟议的实验集中在N-酰基多巴胺，一种新的脂肪酸酰胺，可以作为信号配体的香草素和/或大麻素受体的表征。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（例如辣椒素）通常提高对疼痛的敏感性，N-酰基多巴胺可以内源性地促进或抑制疼痛。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发生情况，以及各种生理和病理生理条件（如炎症）对其形成和生物活性的影响。除了研究大麻素和香草素的机制，我们计划研究我们在体内观察到的NADA的含氧代谢产物。该提案旨在阐明内源性N-酰基多巴胺及其含氧代谢产物的生物学和功能，以增强我们对这类新兴分子的理解，这可能对疼痛的感知和调节很重要。更好地了解这一系统可能会产生新的目标，旨在治疗疼痛和/或炎症的药物开发。

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.