Opioid-Induced Immunomodulation: Consequences for the Experimental Coxsackievirus B3-Induced Myocarditis Model

SIMPLE SUMMARY: Myocarditis is an inflammatory disorder of the heart mainly caused by viruses. To investigate viral myocarditis, the Coxsackievirus B3 (CVB3)-induced myocarditis model is the experimental model used since more than sixty years. In the pathogeneses of viral myocarditis, the subtle balance between pro-and anti-inflammatory immune responses is of great importance for disease manifestation. Parallel to the infection of the heart, experimental CVB3-induced myocarditis results in an infection of the pancreas, causing a severe burden for the challenged animals. In frame of animal welfare, application of analgesics is mandatory. So far, positive as well as negative effects of opioids on the immune system have been described. However, the impact of opioid application on the pathogenesis of experimental CVB3-induced myocarditis has not been investigated yet. Since examinations on disease pathways and new treatment options rely on established models to generate reproducible data, applicability of opioids in experimental CVB3-induced myocarditis needs to be carefully evaluated. For this purpose, we summarized published studies for 13 different opioids and discussed their potential impact on the CVB3-induced myocarditis model. ABSTRACT: Myocarditis is an inflammatory disorder of the heart predominantly caused by infectious agents. Since more than sixty years, the Coxsackievirus B3 (CVB3)-induced myocarditis mouse model is the experimental model used to investigate viral myocarditis. The pathogenesis of viral myocarditis is conceptually a multiphase process, initiated by the infection of cardiomyocytes, followed by activation of the immune system, and resulting in myocardial fibrosis and left ventricular dysfunction. In parallel to the direct infection of the heart, CVB3 replicates in lymphatic organs such as the pancreas. Due to infection of the pancreas, the model of experimental CVB3-induced myocarditis is estimated as a severe burden for the challenged animals. Application of analgesics in frame of the animal welfare act (European directive 2010/63/EU) is more and more becoming a matter of debate. For this purpose, we summarized published studies for 13 different opioids and discussed their potential impact on CVB3-induced myocarditis. In addition, with this summary we also want to provide guidance for researchers beyond the myocarditis field to estimate the impact of opioids on the immune system for their specific model. In the literature, both immunosuppressive as well as immune-activating effects of opioids have been described, but examinations in experimental CVB3-induced myocarditis have still not been reported so far. Based on the existing publications, administration of opioids in experimental CVB3-induced myocarditis might result in more severe disease progression, including higher mortality, or a less pronounced myocarditis model, failing to be used for the establishment of new treatment options. Taken together, the applicability of opioids in experimental CVB3-induced myocarditis and in inflammatory models in general needs to be carefully evaluated and further investigated.