Exploration of Analgesia with Tramadol in the Coxsackievirus B3 Myocarditis Mouse Model

Sandra Pinkert,Ziya Kaya,Nicolas Kelm,Antje Beling,Arnd Heuser,Karin Klingel,Meike Kespohl

doi:10.3390/v13071222

Abstract

Infection of mice with Coxsackievirus B3 (CVB3) triggers inflammation of the heart and this mouse model is commonly used to investigate underlying mechanisms and therapeutic aspects for viral myocarditis. Virus-triggered cytotoxicity and the activity of infiltrating immune cells contribute to cardiac tissue injury. In addition to cardiac manifestation, CVB3 causes cell death and inflammation in the pancreas. The resulting pancreatitis represents a severe burden and under such experimental conditions, analgesics may be supportive to improve the animals’ well-being. Notably, several known mechanisms exist by which analgesics can interfere with the immune system and thereby compromise the feasibility of the model. We set up a study aiming to improve animal welfare while ensuring model integrity and investigated how tramadol, an opioid, affects virus-induced pathogenicity and immune response in the heart. Tramadol was administered seven days prior to a CVB3 infection in C57BL/6 mice and treatment was continued until the day of analysis. Tramadol had no effect on the virus titer or viral pathogenicity in the heart tissue and the inflammatory response, a hallmark of myocardial injury, was maintained. Our results show that tramadol exerts no disruptive effects on the CVB3 myocarditis mouse model and, therefore, the demonstrated protocol should be considered as a general analgesic strategy for CVB3 infection.

Highlights

Myocarditis is an inflammatory disease of the heart, frequently induced by virus infections [1]
This model mimics the general aspects of viral myocarditis in humans and shows primary virus replication in the intestinal organs, the lung or skin, with viruses spreading via the blood stream and subsequent infections of the heart
The increasing emphasis on animal welfare is legitimate, the integrity of the animal model has to be ensured and strategies to improve animal welfare require appropriate in vivo testing. Almost all analgesics, such as nonsteroidal anti-inflammatory drugs and opioids, are thought to interact with the immune system and affect one of the main model-defining hallmarks needed for the proper manifestation of Coxsackievirus B3 (CVB3)-triggered myocarditis [16,27]

Summary

Introduction

Myocarditis is an inflammatory disease of the heart, frequently induced by virus infections [1]. In order to investigate pathogenic mechanisms of virus-induced myocarditis and subsequent inflammatory processes with alterations in the extracellular matrix of the heart, most researchers rely on the Coxsackievirus B3 (CVB3) myocarditis model in mice [2,3,4,5] This model mimics the general aspects of viral myocarditis in humans and shows primary virus replication in the intestinal organs (enterovirus [6] and adenovirus [7]), the lung (influenza virus, some indication for SARS-CoV2 [8,9,10]) or skin (rubella virus [11]), with viruses spreading via the blood stream (viremia) and subsequent infections of the heart. The immune response is required for virus control, but there is consensus that inflammatory processes drive cardiac damage and fibrotic remodeling [4,13]

Methods

Results

Conclusion