Abstract: The ependymal epithelium forms the cerebrospinal fluid barrier, separating the brain and spinal cord from the cerebrospinal fluid. However, in certain regions of the central nervous system, there are neuronal bodies, dendrites, or axons that directly come into contact with the cerebrospinal fluid, constituting what is known as the "cerebrospinal fluid contacting neurons system" (CSF-CNS). The research team led by Professor Zhang Licai successfully employed CB-HRP to selectively label the specialized neuron system that comes into contact with cerebrospinal fluid, pioneeringly naming it as "cerebrospinal fluid contacting nucleus", commonly referred to as the "CSF-contacting nucleus". For the first time, the discovery of the CSF-contacting nucleus provides compelling morphological evidence for the presence of a distinct neural structure within the brain parenchyma that connects with the cerebrospinal fluid, suggesting its potential significance in facilitating material and information exchange between the brain parenchyma and cerebrospinal fluid. After conducting a series of studies on the morphological structure, material expression, gene analysis and function of the CSF-contacting nucleus in rodents and non-human primates, it was discovered that there are fibrous connections between the whole cerebral cortex and subcortical nuclei with the CSF-contacting nucleus. It may participate in the functional regulation of pain, cognition, learning and memory, emotion, addiction, stress and anxiety responses, visceral activity, olfaction, vision processing and perception, auditory processing and perception as well as motor control and coordination. Additionally, it is involved in homeostasis regulation including energy balance and body fluid balance maintenance along with sleep-wake cycle regulation and biological rhythm synchronization. Current experiments have confirmed that the CSF-contacting nucleus is related to pain, morphine dependence and withdrawal, learning and memory and stress. This article provides a comprehensive review of the neurobiological characteristics and recent advancements in pain regulation of the CSF-contacting nucleus. The aim is to offer new insights into the study of pain regulation within the brain-cerebrospinal fluid bidirectional regulatory pathway, with a specific focus on the role of the CSF-contacting nucleus as a bridge structure. Additionally, this research aims to propose novel approaches for pain management and related disorders in the future.