Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.25.060939v1?rss=1 Authors: Mikhailov, N., Koroleva, K., Abdollahzadeh, A., Giniatullina, R., Gafurov, O., Malm, T., Sierra Lopez, A., Tohka, J., Noe, F. M., Giniatullin, R. Abstract: Background: A system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in cleaning of the brain via cerebro-spinal fluid drainage. As meninges are an important tissue involved in the origin of migraine pain, we hypothesized that malfunctioning of a cleaning lymphatic system should affect the functional properties of meningeal nociception. To test this hypothesis, we studied migraine-related nociceptive and inflammatory mechanisms in the meninges, in a mouse model of primary lymphedema (K14-VEGFR3-Ig mice) characterized by the lack of functional meningeal lymphatic system. Methods: To study the migraine-related nociceptive and inflammatory mechanisms we recorded spiking activity from meningeal fibers of the trigeminal nerve, estimated the local mast cells infiltration, calcitonin gene-related peptide (CGRP) and cytokine levels (basal and under stimulating conditions), as well as the dura mater innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). Results: We found that the level of CGRP and the production of TNF , which both are implicated in migraine, were reduced in meninges of K14 mice. There was a trend of having a larger number of dural mast cells, consistent with the increased level of the mast cell activator MCP-1 found in these animals. In addition, we found an increased spontaneous and ATP-induced nociceptive firing in the meningeal afferents of mice lacking meningeal lymphatic system. However, the patterns of trigeminal innervation in meninges remained unchanged. Conclusions: In summary, the lack of meningeal lymphatic system leads to a new balance between pro- and anti-inflammatory mechanisms implicated in peripheral nociception, affecting key cellular and humoral factors implicated in migraine. Copy rights belong to original authors. Visit the link for more info