CSF outflow through the cribriform plate near the olfactory nerves and the outflow along brain and spinal nerves are together known as peripheral CSF outflow pathway (PCOP). It is still not clear whether the PCOP has pathogenetic relevance. Our previous clinical observations have indicated that CSF may interact with nerves along the PCOP and in this article we present our finding of CSF outflow demonstrated by myelography in a single patient. We also discuss unexplained experimental pain pathomechanisms against the background of the PCOP hypothesis. We observed that CSF flowed along lumbar nerves in distal direction at a speed of about 10 cm per hour on its way through the tissues, mainly muscles. Total CSF outflow volume at the lumbar site was remarkable. CSF outflow at lumbar nerves was also documented by neuroradiology. It is plausible that CSF signaling serves for interaction with nerves along the PCOP, which could explain previously unknown pathomechanisms in pain generation. Experimental findings of tactile pain hypersensitivity within lumbosacral pain pathways could be explained by releasing of molecules, microparticles, or exosomes into the CSF by mast cells, which then move with CSF outflow along the PCOP and interact with nerves, initiating even retrograde synaptic stripping.