Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis

Usman Barlass, Raini Dutta, Hassam Cheema, John George, Archana Sareen, Ajay Dixit, Zuobiao Yuan, Bhuwan Giri, Jingjing Meng, Santanu Banerjee, Sulagna Banerjee, Vikas Dudeja, Rajinder Dawra, Sabita Roy, Ashok Saluja

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)719-727
Number of pages9
JournalGut
Volume67
Issue number4
DOIs
StatePublished - Apr 1 2018

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Pancreatitis
Morphine
Regeneration
Naltrexone
Hedgehogs
Opioid Receptors
Opioid Analgesics
Bacterial Translocation
Therapeutics
Ceruletide
Narcotic Antagonists
mu Opioid Receptor
Pain Management
Bacteremia
Knockout Mice
Analgesia
Fluorescent Antibody Technique
Arginine
Immune System
Permeability

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis. / Barlass, Usman; Dutta, Raini; Cheema, Hassam; George, John; Sareen, Archana; Dixit, Ajay; Yuan, Zuobiao; Giri, Bhuwan; Meng, Jingjing; Banerjee, Santanu; Banerjee, Sulagna; Dudeja, Vikas; Dawra, Rajinder; Roy, Sabita; Saluja, Ashok.

In: Gut, Vol. 67, No. 4, 01.04.2018, p. 719-727.

Research output: Contribution to journalArticle

Barlass, Usman ; Dutta, Raini ; Cheema, Hassam ; George, John ; Sareen, Archana ; Dixit, Ajay ; Yuan, Zuobiao ; Giri, Bhuwan ; Meng, Jingjing ; Banerjee, Santanu ; Banerjee, Sulagna ; Dudeja, Vikas ; Dawra, Rajinder ; Roy, Sabita ; Saluja, Ashok. / Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis. In: Gut. 2018 ; Vol. 67, No. 4. pp. 719-727.
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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.",
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T1 - Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis

AU - Barlass, Usman

AU - Dutta, Raini

AU - Cheema, Hassam

AU - George, John

AU - Sareen, Archana

AU - Dixit, Ajay

AU - Yuan, Zuobiao

AU - Giri, Bhuwan

AU - Meng, Jingjing

AU - Banerjee, Santanu

AU - Banerjee, Sulagna

AU - Dudeja, Vikas

AU - Dawra, Rajinder

AU - Roy, Sabita

AU - Saluja, Ashok

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

AB - 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.

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