http://www.ncbi.nlm.nih.gov/pubmed/25165054 full text http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157386/ INTRODUCTION: THE PERIPHERAL CSF OUTFLOW PATHWAYS (PCOP) It has been traditionally accepted that cerebrospinal fluid (CSF) flows from the subarachnoid spaces (SAS) through the cribriform plate into the cervical lymphatics, and similarly, along all brain nerves and all peripheral nerves into the respective tissues. This CSF outflow can transport antigens from CSF spaces to the extracellular fluid of peripheral tissues, which are then collected into the lymphatic system (1). CSF outflow through the cribriform plate to cervical lymphatics has been shown to be important for CNS-specific immune responses (2,3), but CSF outflow along (other) brain nerves and spinal nerves has been only poorly investigated. Our previous research investigated low level neuroinflammation (LLNI) subgroups in severe psychiatric disorders (4). Affective and schizophrenia spectrum disorders may be accompanied by pain and other sensory symptoms (5), which could be explained at least in part by LLNI pathomechanisms that arise from an interaction between CSF and peripheral nerves along the PCOP. It is also suggested that PCOP-associated symptoms prevail in classic neuroinflammation and possibly even in systemic inflammation (6). CSF has been found to have an important signaling function; CNS volume transmission involves signaling within the CNS extracellular spaces with a link to CSF signaling (7). PCOP HYPOTHESIS AS A POSSIBLE EXPLANATION FOR WIDESPREAD TACTILE PAIN HYPERSENSITIVITY Levy et al (12) investigated widespread tactile pain hypersensitivity from activated trigemino-cervical and lumbosacral pain pathways induced by mast cell degranulation, but it remained unsolved what mechanism mediated hind paw hypersensitivity; for example with the available hypothesis it was difficult to explain the details of the time course of the changes. We would like to contribute to these observations by proposing a following scenario involving the PCOP. Pathways of cerebrospinal fluid outflow: a deeper understanding of resorption. http://www.ncbi.nlm.nih.gov/pubmed/25398655 Research into the Physiology of Cerebrospinal Fluid Reaches a New Horizon: Intimate Exchange between Cerebrospinal Fluid and Interstitial Fluid May Contribute to Maintenance of Homeostasis in the Central Nervous System. http://www.ncbi.nlm.nih.gov/pubmed/27245177 full http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945600/ Short summary 1.Key et al. indicated the arachnoid granulation or villi and retro-orbital tissues as pathways for CSF absorption and also showed that dye administered into the subarachnoid space reaches the cervical lymph node. 2.Various locations within the central nervous system such as the arachnoid granulation or villi, periphery of some cranial nerves including the olfactory nerve, spinal nerve root, and capillaries of the brain parenchyma are postulated as routes for CSF absorption. 3.CSF that exits from the subarachnoid space to the dura mater and epidural space is known to travel to the systemic circulation via the venous sinus or to the cervical lymphatic system through the nasal mucosa or meningeal lymphatic vessels (Fig. 5). 4.The route in which CSF migrates from the subarachnoid space to the meningeal lymphatic vessel is yet unknown, and further elucidation is awaited.