Differential effect of histamine 3 receptor-active agents on brain, but not peritoneal, mast cell activation

The activation of presynaptic histamine 3 (H-3) receptors inhibits the rele ase of histamine and other neurotransmitters from central nervous system ne urons. Rat brain mast cells (MCs) release histamine and 5-hydroxytryptamine (5-HT) in response to neuropeptides and neurotransmitters secreted from ad jacent neurons. Dura MCs also degranulate in response to antidromic trigemi nal nerve stimulation and with acute psychological stress. Such findings ha ve implicated brain MCs in certain neuroinflammatory disorders, such as mig raines. We investigated the ultrastructural appearance of control and stimu lated thalamic/hypothalamic (brain) MCs before and after treatment with the H-3 receptor agonist N-alpha-methylhistamine (N-alpha-mH) and the H-3 rece ptor antagonist thioperamide (Th). Ultrastructural investigation of brain M Cs stimulated with compound 48/80 revealed extensive intragranular changes that paralleled 5-HT secretion but without degranulation by exocytosis typi cal of connective tissue MCs. N-alpha-mH significantly reduced these morpho logical changes, as well as 5-HT release from brain MCs and neurons stimula ted with KCl; conversely, Th augmented both histamine and 5-HT release from brain neurons and MCs. Neither N-alpha-mH nor Th had any effect on periton eal MCs. Simultaneous addition of both drugs largely antagonized each other 's effects on brain MC activation and 5-HT secretion. Ultrastructural obser vations and lack of lactic dehydrogenase release in the perfusate excluded any cytotoxic effect. The ability of H-3 agonists to inhibit brain MC activ ation, as well as secretion of 5-HT from both brain MCs and neurons, may be useful in the management of migraines.