In summary, mast cell interactions in the nervous system are relevant to both physiological processes (ie reproduction) and pathologic states (ie inflammatory demyelination, painful disorders, toxic and metabolic disease, and tumor angiogenesis). Their physiologic roles may contribute to gender-related vulnerability to inflammatory disease and may modulate sensitivity to pain. Mast cells are universally involved in tissue repair and they release and respond to trophic factors such as NGF. These cells also produce and react to cytokines, and thus appear to play a role in tissue degeneration as well as repair. In certain neurological diseases, ie multiple sclerosis and Guillain-Barré syndrome, the ability of mast cell proteases to degrade specific myelin proteins suggests that these cells are agents, rather than bystanders, in the demyelinative process. Even more intriguing is their recently identified capacity to process bacterial antigen as efficiently as activated macrophages, suggesting that a more critical role than previously suspected might be considered for mast cells in CNS and PNS demyelination. In experimental metabolic disorders such as galactose intoxication and thiamine deficiency, mast cells appear to play a pathogenic role. Thus, in galactose intoxication, altered BNB vascular permeability occurs in conjunction with mast cell proliferation and degranulation, while in thiamine deficiency, increased histamine levels have been reported in the rat thalamus (79) and are associated with cell death and proliferation as well as mast cell degranulation (Powell and Langlais, unpublished observations). Structural interactions between mast cells and a variety of other cells have been observed, as well as close approximation of mast cells to nerve endings in tissues in which mast cells are especially active. Due to their paracrine nature, mast cells can modulate events in their microenvironment through explosive degranulation, piecemeal degranulation, or" transgranulation" as they insert granules into neighboring cells. Lastly, these cells play specific roles in reparative processes, eg angiogenesis, and are active in neoplastic states, including von Recklinghausen's disease (neurofibromatosis). Their involvement may have been underestimated in neuropathological studies, to date, by a reliance on staining techniques that are inadequate for identifying degranulated and therefore activated mast cells (4). More exacting histochemical and immunostaining procedures will help to fully realize the extent of their participation in physiological and pathological processes.