Gyires Klára, Zádori Zoltán S
Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad ter 4., 1089, Budapest, Hungary.
Curr Neuropharmacol. 2016;14(8):935-951. doi: 10.2174/1570159x14666160303110150.
Modulating the activity of the endocannabinoid system influences various gastrointestinal physiological and pathophysiological processes, and cannabinoid receptors as well as regulatory enzymes responsible for the synthesis or degradation of endocannabinoids representing potential targets to reduce the development of gastrointestinal mucosal lesions, hemorrhage and inflammation. Direct activation of CB1 receptors by plant-derived, endogenous or synthetic cannabinoids effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms. Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduces the gastric mucosal lesions induced by NSAIDs in a CB1 receptor-dependent fashion. Dual inhibition of FAAH and cyclooxygenase enzymes induces protection against both NSAID-induced gastrointestinal damage and intestinal inflammation. Moreover, in intestinal inflammation direct or indirect activation of CB1 and CB2 receptors exerts also multiple beneficial effects. Namely, activation of both CB receptors was shown to ameliorate intestinal inflammation in various murine colitis models, to decrease visceral hypersensitivity and abdominal pain, as well as to reduce colitis-associated hypermotility and diarrhea. In addition, CB1 receptors suppress secretory processes and also modulate intestinal epithelial barrier functions. Thus, experimental data suggest that the endocannabinoid system represents a promising target in the treatment of inflammatory bowel diseases, and this assumption is also confirmed by preliminary clinical studies.
调节内源性大麻素系统的活性会影响各种胃肠道生理和病理生理过程，大麻素受体以及负责内源性大麻素合成或降解的调节酶是减少胃肠道黏膜损伤、出血和炎症发生的潜在靶点。植物源性、内源性或合成大麻素直接激活CB1受体可有效减少胃酸分泌和胃运动活性，并减少由应激、幽门结扎、非甾体抗炎药（NSAIDs）或酒精诱导的胃黏膜损伤的形成，部分通过外周机制，部分通过中枢机制。同样，通过其代谢酶（FAAH、MAGL）的全局作用或外周限制抑制剂或其细胞摄取抑制剂提高内源性大麻素水平来间接激活大麻素受体，以CB1受体依赖的方式减少NSAIDs诱导的胃黏膜损伤。FAAH和环氧化酶的双重抑制可诱导对NSAIDs诱导的胃肠道损伤和肠道炎症的保护作用。此外，在肠道炎症中，CB1和CB2受体的直接或间接激活也发挥多种有益作用。具体而言，在各种小鼠结肠炎模型中，两种CB受体的激活均显示可改善肠道炎症，降低内脏超敏反应和腹痛，并减少结肠炎相关的运动亢进和腹泻。此外，CB1受体抑制分泌过程并调节肠道上皮屏障功能。因此，实验数据表明内源性大麻素系统是治疗炎症性肠病的一个有前景的靶点，这一假设也得到了初步临床研究的证实。
