Michalski Christoph W, Laukert Tamara, Sauliunaite Danguole, Pacher Pál, Bergmann Frank, Agarwal Nitin, Su Yun, Giese Thomas, Giese Nathalia A, Bátkai Sándor, Friess Helmut, Kuner Rohini
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Gastroenterology. 2007 May;132(5):1968-78. doi: 10.1053/j.gastro.2007.02.035. Epub 2007 Feb 21.
BACKGROUND & AIMS: The functional involvement of the endocannabinoid system in modulation of pancreatic inflammation, such as acute pancreatitis, has not been studied to date. Moreover, the therapeutic potential of cannabinoids in pancreatitis has not been addressed.
We quantified endocannabinoid levels and expression of cannabinoid receptors 1 and 2 (CB1 and CB2) in pancreas biopsies from patients and mice with acute pancreatitis. Functional studies were performed in mice using pharmacological interventions. Histological examination, serological, and molecular analyses (lipase, myeloperoxidase, cytokines, and chemokines) were performed to assess disease pathology and inflammation. Pain resulting from pancreatitis was studied as abdominal hypersensitivity to punctate von Frey stimuli. Behavioral analyses in the open-field, light-dark, and catalepsy tests were performed to judge cannabinoid-induced central side effects.
Patients with acute pancreatitis showed an up-regulation of cannabinoid receptors and elevated levels of endocannabinoids in the pancreas. HU210, a synthetic agonist at CB1 and CB2, abolished abdominal pain associated with pancreatitis and also reduced inflammation and decreased tissue pathology in mice without producing central, adverse effects. Antagonists at CB1- and CB2-receptors were effective in reversing HU210-induced antinociception, whereas a combination of CB1- and CB2-antagonists was required to block the anti-inflammatory effects of HU210 in pancreatitis.
In humans, acute pancreatitis is associated with up-regulation of ligands as well as receptors of the endocannabinoid system in the pancreas. Furthermore, our results suggest a therapeutic potential for cannabinoids in abolishing pain associated with acute pancreatitis and in partially reducing inflammation and disease pathology in the absence of adverse side effects.
内源性大麻素系统在调节胰腺炎症（如急性胰腺炎）中的功能作用迄今尚未得到研究。此外，大麻素在胰腺炎中的治疗潜力也未得到探讨。
我们对急性胰腺炎患者和小鼠胰腺活检组织中的内源性大麻素水平以及大麻素受体1和2（CB1和CB2）的表达进行了定量分析。在小鼠中使用药理学干预进行功能研究。进行组织学检查、血清学和分子分析（脂肪酶、髓过氧化物酶、细胞因子和趋化因子）以评估疾病病理和炎症情况。将胰腺炎引起的疼痛作为腹部对点状von Frey刺激的超敏反应进行研究。在旷场试验、明暗试验和僵住试验中进行行为分析，以判断大麻素引起的中枢副作用。
急性胰腺炎患者胰腺中大麻素受体上调，内源性大麻素水平升高。HU210是一种CB1和CB2的合成激动剂，可消除与胰腺炎相关的腹痛，还可减轻小鼠的炎症并降低组织病理学损伤，且不产生中枢不良反应。CB1和CB2受体拮抗剂可有效逆转HU210诱导的抗伤害感受作用，而需要联合使用CB1和CB2拮抗剂才能阻断HU210在胰腺炎中的抗炎作用。
在人类中，急性胰腺炎与胰腺内源性大麻素系统的配体以及受体上调有关。此外，我们的结果表明，大麻素在消除与急性胰腺炎相关的疼痛以及在无不良副作用的情况下部分减轻炎症和疾病病理方面具有治疗潜力。
