McIlwrath SL, Starr ME, High AE, Saito H, Westlund KN. Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain’s pain circuitry. World J Gastroenterol 2021; 27(9): 794-814 [PMID: 33727771 DOI: 10.3748/wjg.v27.i9.794]
Corresponding Author of This Article
Sabrina L McIlwrath, PhD, Senior Scientist, Research Service, New Mexico Veterans Affairs Healthcare System, 1501 San Pedro SE, Albuquerque, NM 87108, United States. sabrina.mcilwrath@va.gov
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
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McIlwrath SL, Starr ME, High AE, Saito H, Westlund KN. Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain’s pain circuitry. World J Gastroenterol 2021; 27(9): 794-814 [PMID: 33727771 DOI: 10.3748/wjg.v27.i9.794]
World J Gastroenterol. Mar 7, 2021; 27(9): 794-814 Published online Mar 7, 2021. doi: 10.3748/wjg.v27.i9.794
Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain’s pain circuitry
Sabrina L McIlwrath, Marlene E Starr, Abigail E High, Hiroshi Saito, Karin N Westlund
Sabrina L McIlwrath, Karin N Westlund, Research Service, New Mexico Veterans Affairs Healthcare System, Albuquerque, NM 87108, United States
Marlene E Starr, Hiroshi Saito, Department of Surgery, University of Kentucky, Lexington, KY 40536, United States
Abigail E High, College of Liberal Arts, University of Texas, Austin, TX 78712, United States
Karin N Westlund, Department of Anesthesiology and Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States
Author contributions: McIlwrath SL performed the animal experiments, data analysis, produced the figures, wrote the manuscript; Starr ME assisted with animal caerulein dosing and read the manuscript; High AE analyzed the microglial morphology in the brain sections; Saito H designed the study, read and edited this manuscript; Westlund KN designed the study, read and edited this manuscript; all authors discussed the results, commented on the manuscript, and approved the final version of the article.
Supported byUnited States Department of Veterans Affairs, VA Merit Grant, No. BX002695; and United States National Institute of Health, No. R01AG055359, No. R01GM126181 and No. R01NS39041-15.
Institutional animal care and use committee statement: This study was reviewed and approved by the Institutional Animal Care and Use Committee of the University of Kentucky (IACUC Protocol No. 2010-0736). The animal care facility of the University of Kentucky is accredited by AALAC.
Conflict-of-interest statement: The authors have nothing to disclose. This communication does not necessarily reflect the views of the Department of Veterans Affairs or the United States government.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Corresponding author: Sabrina L McIlwrath, PhD, Senior Scientist, Research Service, New Mexico Veterans Affairs Healthcare System, 1501 San Pedro SE, Albuquerque, NM 87108, United States. sabrina.mcilwrath@va.gov
Received: September 11, 2020 Peer-review started: September 11, 2020 First decision: November 25, 2020 Revised: December 8, 2020 Accepted: January 15, 2021 Article in press: January 15, 2021 Published online: March 7, 2021 Processing time: 172 Days and 11.8 Hours
ARTICLE HIGHLIGHTS
Research background
Pancreatitis is a multifactorial, progressive disease developing from acute to recurring and chronic pancreatitis with increased risk of pancreatic cancer. Chief clinical complaint is intractable abdominal pain that does not respond to medication/ narcotics.
Research motivation
Pancreatitis-induced pain is driven by peripheral tissue damage, inflammation, and oxidative stress. This abdominal pain is only poorly alleviated with present pharmacological interventions, including opioid analgesics, which pose a high risk of addiction and other serious adverse events such as bowel dysfunction, increasing of abdominal pain, and respiratory suppression.
Research objectives
The present investigation had two aims: (1) Can the antioxidant and mitochondrial enhancer ALC attenuate pain- and anxiety-like behavioral changes during 6 wk of recurrent acute pancreatitis; and (2) Does recurrent acute pancreatitis activate brain microglia along the pain neuraxis and contribute to central sensitization and the initiation/maintenance of chronic pain.
Research methods
The CAE-induced pancreatitis model with progression to chronic pancreatitis was employed in male C57BL/6J mice to investigate pain- and anxiety-like behaviors during a 6-week time course and the efficacy of ALC to alleviate them determined. Post-mortem analysis of microglial activation in pain- and anxiety-related brain regions from naïve animals was compared to vehicle-treated mice with CAE-induced pancreatitis.
Research results
The persistent recurring pancreatitis model induces mechanical and heat hypersensitivity, as well as pain related anxiety measures. Vehicle-treated animals with CAE-induced pancreatitis developed pain- and anxiety-like behaviors. Treatment with ALC attenuated hypersensitivity but had limited efficacy in reducing anxiety-like behaviors. Activated microglial were identified in hippocampus, thalamus, hypothalamus and amygdala of vehicle-treated mice with CAE-induced pancreatitis, but not in the somatosensory cortex.
Research conclusions
Acute recurrent pancreatitis is accompanied by brain microglia activation along the limbic pain- and anxiety-neuraxis in response to the persisting pancreatic pain.
Research perspectives
Pharmacological approaches to reduce microglial activation may identify novel non-opioid approaches for pain treatment during pancreatitis.
