Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA.
Gut. 2018 Apr;67(4):600-602. doi: 10.1136/gutjnl-2017-313717. Epub 2017 Jun 22.
Opioids such as morphine are widely used for the management of pain associated with acute pancreatitis. Interestingly, opioids are also known to affect the immune system and modulate inflammatory pathways in non-pancreatic diseases. However, the impact of morphine on the progression of acute pancreatitis has never been evaluated. In the current study, we evaluated the impact of morphine on the progression and severity of acute pancreatitis.
Effect of morphine treatment on acute pancreatitis in caerulein, L-arginine and ethanol-palmitoleic acid models was evaluated after induction of the disease. Inflammatory response, gut permeability and bacterial translocation were compared. Experiments were repeated in mu (µ) opioid receptor knockout mice (MORKO) and in wild-type mice in the presence of opioid receptor antagonist naltrexone to evaluate the role of µ-opioid receptors in morphine's effect on acute pancreatitis. Effect of morphine treatment on pathways activated during pancreatic regeneration like sonic Hedgehog and activation of embryonic transcription factors like pdx-1 and ptf-1 were measured by immunofluorescence and quantitative PCR.
Histological data show that treatment with morphine after induction of acute pancreatitis exacerbates the disease with increased pancreatic neutrophilic infiltration and necrosis in all three models of acute pancreatitis. Morphine also exacerbated acute pancreatitis-induced gut permeabilisation and bacteraemia. These effects were antagonised in the MORKO mice or in the presence of naltrexone suggesting that morphine's effect on severity of acute pancreatitis are mediated through the µ-opioid receptors. Morphine treatment delayed macrophage infiltration, sonic Hedgehog pathway activation and expression of pdx-1 and ptf-1.
Morphine treatment worsens the severity of acute pancreatitis and delays resolution and regeneration. Considering our results, the safety of morphine for analgesia during acute pancreatitis should be re-evaluated in future human studies.
吗啡等阿片类药物被广泛用于治疗与急性胰腺炎相关的疼痛。有趣的是，阿片类药物也已知会影响免疫系统，并调节非胰腺疾病中的炎症途径。然而，吗啡对急性胰腺炎进展的影响从未被评估过。在本研究中，我们评估了吗啡对急性胰腺炎进展和严重程度的影响。
在诱导疾病后，评估了吗啡治疗对胆囊收缩素、精氨酸和乙醇-棕榈油酸急性胰腺炎模型中急性胰腺炎的影响。比较了炎症反应、肠道通透性和细菌易位。在存在阿片受体拮抗剂纳曲酮的情况下，在 mu (µ) 阿片受体敲除小鼠 (MORKO) 和野生型小鼠中重复了实验，以评估 µ 阿片受体在吗啡对急性胰腺炎作用中的作用。通过免疫荧光和定量 PCR 测量吗啡治疗对胰腺再生过程中激活的途径（如 sonic Hedgehog）和激活的胚胎转录因子（如 pdx-1 和 ptf-1）的影响。
组织学数据显示，在急性胰腺炎诱导后给予吗啡治疗会加剧疾病，在所有三种急性胰腺炎模型中均增加胰腺中性粒细胞浸润和坏死。吗啡还加剧了急性胰腺炎诱导的肠道通透性和菌血症。这些作用在 MORKO 小鼠或纳曲酮存在时被拮抗，表明吗啡对急性胰腺炎严重程度的影响是通过 µ 阿片受体介导的。吗啡治疗延迟了巨噬细胞浸润、sonic Hedgehog 途径的激活以及 pdx-1 和 ptf-1 的表达。
吗啡治疗会加重急性胰腺炎的严重程度，并延迟缓解和再生。考虑到我们的结果，未来的人类研究中应重新评估吗啡在急性胰腺炎期间镇痛的安全性。
