Background and aims Gap junction-coupled cells form networks in different organs in the body. These networks can be affected by inflammatory stimuli and become dysregulated. Cell signaling is also changed through connexin-linked gap junctions. This alteration affects the surrounding cells and extracellular matrix in organs. These changes can cause the spread of inflammatory substances, thus affecting other network-linked cells in other organs in the body, which can give rise to systemic inflammation, which in turn can lead to pain that can turn into chronic. Methods This is a review based on literature search and our own research data of inflammatory stimuli that can affect different organs and particularly gap-junction-coupled cells throughout the body. Conclusions A remaining question is which cell type or tissue is first affected by inflammatory stimuli. Can endotoxin exposure through the air, water and body start the process and are mast cells the first target cells that have the capacity to alter the physiological status of gap junction-coupled cells, thereby causing breakdown of different barrier systems? Implications Is it possible to address the right cellular and biochemical parameters and restore inflammatory systems to a normal physiological level by therapeutic strategies?