Enkephalin-Encoding Herpes Simplex Virus-1 Decreases Inflammation and Hotplate Sensitivity in a Chronic Pancreatitis Model

Hong Yang,Rong Chu,Ying Lu,Karin N Westlund,Steven P Wilson,David C Yeomans,Yong Ren,Terry A Mcnearney

doi:10.1186/1744-8069-4-8

Abstract

BackgroundA chronic pancreatitis model was developed in young male Lewis rats fed a high-fat and alcohol liquid diet beginning at three weeks. The model was used to assess time course and efficacy of a replication defective herpes simplex virus type 1 vector construct delivering human cDNA encoding preproenkephalin (HSV-ENK).ResultsMost surprising was the relative lack of inflammation and tissue disruption after HSV-ENK treatment compared to the histopathology consistent with pancreatitis (inflammatory cell infiltration, edema, acinar cell hypertrophy, fibrosis) present as a result of the high-fat and alcohol diet in controls. The HSV-ENK vector delivered to the pancreatic surface at week 3 reversed pancreatitis-associated hotplate hypersensitive responses for 4–6 weeks, while control virus encoding β-galactosidase cDNA (HSV-β-gal) had no effect. Increased Fos expression seen bilaterally in pain processing regions in control animals with pancreatitis was absent in HSV-ENK-treated animals. Increased met-enkephalin staining was evident in pancreas and lower thoracic spinal cord laminae I–II in the HSV-ENK-treated rats.ConclusionThus, clear evidence is provided that site specific HSV-mediated transgene delivery of human cDNA encoding preproenkephalin ameliorates pancreatic inflammation and significantly reduces hypersensitive hotplate responses for an extended time consistent with HSV mediated overexpression, without tolerance or evidence of other opiate related side effects.

Highlights

A chronic pancreatitis model was developed in young male Lewis rats fed a high-fat and alcohol liquid diet beginning at three weeks
Pancreas of HSV-1 with preproenkephalin cDNA (HSV-ENK)-treated rats has normal histopathology Histological examination of pancreata at ten weeks in rats fed with high fat and alcohol diets and treated with vehicle (Fig. 1B) or HSV-β-gal (Fig. 1C) demonstrated tissue edema, steatosis, inflammatory cell infiltration, fibrosis, and acinar necrosis in all rats from these two groups
The pancreata of rats fed with alcohol and high fat diet but treated with HSV-ENK (Fig. 1D) showed reduced inflammatory cell infiltration and preservation of pancreatic tissue architecture

Summary

Introduction

A chronic pancreatitis model was developed in young male Lewis rats fed a high-fat and alcohol liquid diet beginning at three weeks. Over 50% of patients with idiopathic or alcoholic pancreatitis report chronic severe pain, responsive initially to morphine or synthetic opioids, but subject to development of tolerance (page number not for citation purposes). Site-specific management of pain from chronic pancreatitis would significantly impact patients' pain levels, physical functioning, quality of life, general health and survival given the high rate of suicide in patients with this condition. We used 40-day-old Lewis rats fed a commercial high fat liquid diet with 6% alcohol. The combined highfat and alcohol diet given to younger animals greatly accelerated the induction of pancreatitis and allowed persistence through the end of the study at 10 weeks. Hypersensitive thermal responses developed in three weeks and remained through ten weeks allowing study of the HSV overexpression time course

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Discussion

Conclusion