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Original Article
Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis
  1. Usman Barlass,
  2. Raini Dutta,
  3. Hassam Cheema,
  4. John George,
  5. Archana Sareen,
  6. Ajay Dixit,
  7. Zuobiao Yuan,
  8. Bhuwan Giri,
  9. Jingjing Meng,
  10. Santanu Banerjee,
  11. Sulagna Banerjee,
  12. Vikas Dudeja,
  13. Rajinder K Dawra,
  14. Sabita Roy,
  15. Ashok K Saluja
  1. Sylvester Comprehensive Cancer Center Department of Surgery, University of Miami, Miami, Florida, USA
  1. Correspondence to Dr Ashok K Saluja, Department of Surgery, University of Miami, 1120 NW 14th St, Miami, FL 33136, USA; asaluja{at}miami.edu

Abstract

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.

  • Morphine
  • pancreatitis
  • regeneration
  • hedgehog
  • PDX-1
  • PTF-1
  • macrophages
  • severity

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Footnotes

  • Contributors AKS and SR conceptualised the study. RKD, VD and SuB designed the experiments. UB, RD, HC, JG, AD, AS, ZY, BG and JM conducted the experiments. AKS, RKD, VD, SaB and SuB interpreted the results. AKS, RKD, VD, SR and SuB drafted the manuscript. AKS, RKD, VD, SR and SuB revised the manuscript. AKS is overall contents guarantor.

  • Funding This work was supported, in whole or in part, by National Institutes of Health DK058694, DK093047, and DK092145 (to AKS), DA034582, K05DA033881 (to SR) and intramural support from Department of Surgery, University of Minnesota.

  • Competing interests AKS is the co-founder and the Chief Scientific Officer of Minneamrita Therapeutics LLC. SB is a consultant with Minneamrita Therapeutics LLC. AKS is consultant for Sun BioPharma. These relationships have been reviewed and managed by the University of Minnesota and University of Miami in accordance with their conflict of interest policies. Other authors have nothing to disclose.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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