Background 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. Methods 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. Results 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. Conclusion 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.

中文翻译：

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吗啡加重急性胰腺炎小鼠模型的严重程度并阻止胰腺再生

背景 吗啡等阿片类药物广泛用于治疗与急性胰腺炎相关的疼痛。有趣的是，还已知阿片类药物会影响免疫系统并调节非胰腺疾病中的炎症通路。然而，从未评估过吗啡对急性胰腺炎进展的影响。在目前的研究中，我们评估了吗啡对急性胰腺炎进展和严重程度的影响。方法 在诱发疾病后评估吗啡治疗对caerulein、L-精氨酸和乙醇-棕榈油酸模型急性胰腺炎的影响。比较了炎症反应、肠道通透性和细菌易位。在阿片受体拮抗剂纳曲酮存在的情况下，在 mu (µ) 阿片受体敲除小鼠 (MORKO) 和野生型小鼠中重复实验，以评估 µ-阿片受体在吗啡对急性胰腺炎的作用中的作用。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通路（如 sonic Hedgehog）和胚胎转录因子（如 pdx-1 和 ptf-1）激活的影响。结果 组织学数据表明，在急性胰腺炎的所有三种模型中，在急性胰腺炎诱导后用吗啡治疗会使疾病恶化，胰腺中性粒细胞浸润和坏死增加。吗啡还加剧了急性胰腺炎引起的肠道通透性和菌血症。这些作用在 MORKO 小鼠中或在纳曲酮存在下被拮抗，这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。吗啡治疗延迟巨噬细胞浸润、声波 Hedgehog 通路激活和 pdx-1 和 ptf-1 的表达。结论吗啡治疗加重了急性胰腺炎的严重程度，延缓了消退和再生。考虑到我们的结果，在未来的人体研究中应重新评估吗啡在急性胰腺炎期间镇痛的安全性。结论吗啡治疗加重了急性胰腺炎的严重程度，延缓了消退和再生。考虑到我们的结果，在未来的人体研究中应重新评估吗啡在急性胰腺炎期间镇痛的安全性。结论吗啡治疗加重了急性胰腺炎的严重程度，延缓了消退和再生。考虑到我们的结果，在未来的人体研究中应重新评估吗啡在急性胰腺炎期间镇痛的安全性。