Ehlers-Danlos syndromes (EDS) are a group of monogenic heritable connective tissue disorders that are caused by genetic defects in several genes affecting the extracellular matrix (ECM). Chronic pain is a major reason why most EDS patients seek medical help. Despite its high prevalence, little is known about the precise origins and mechanisms contributing to EDS-related pain and the pain is usually inadequately controlled by currently used treatments. An important reason for this is the lack of studies investigating the existing knowledge gaps. Animal models can give valuable insights into mechanisms and pathways that are affected in human disorders and in pain. Zebrafish has emerged as a promising animal model to reliably study pain-related behavior and associated mechanisms since their nervous system shows great similarity to humans. We will use existing and novel zebrafish models with defects covering two classes of ECM molecules defective in EDS: collagens (col1a2-/- and col5a1+/-) and proteoglycans (b4galt7-/-, b3galt6-/- and chst14-/-) to assess whether these EDS models show a pain-related phenotype. First, the spontaneous free-swimming behavior of young and adult zebrafish will be carefully monitored and analyzed. If pain-related behavior is observed, we will try to ameliorate the observed pain-related behavior by administering several types of pain medication. In addition, alterations in neuronal development will be evaluated by crossing EDS zebrafish with a specific reporter line allowing to visualize the nervous system. When successful, the data gained from this proposal will set the stage for further in depth pain research. Demonstration of pain-like behavior in zebrafish will propel this research further with an important potential toward screening for therapeutic agents which will result in safer and more efficient pain relief.