- RATIONALE FOR THE USE OF STUDY DRUG IN THE TREATMENT OF STUDY DISEASE In 1991, Guerrero, et al. carried out an initial study that provided evidence for the beneficial effects of histamine in migraine prophylaxis (Millan-Guerrero RO, 1999). Their data showed that subcutaneous administration of low doses (1-10 ng) of histamine induced significant relief from migraine symptoms, with no secondary effects. The possible mechanisms of histamine migraine prophylaxis, can be explained by histamine control of mast cells; the antidromic stimulation of trigeminal nerve endings induces the release of substance P and other neuromodulatory peptides, which in turn stimulate the release of histamine from mast cells. In meningeal blood vessels, activation of H1-receptors by histamine, results in vasodilatation and plasma protein extravasation, causing neurogenic inflammation (Akerman S, 2002). Krabbe and Olesen (Krabbe AA, 1980) and Lassen et al. (Lassen LH, 1995) showed that on migrainous subjects, intravenous administration of relatively high doses of histamine (0.5 mg/kg per minute for 20 min) caused an immediate headache during the infusion, followed by a delayed migraine attack which was abolished by pre-treatment with the H1-R antagonist, mepyramine. However, degranulation of mast cells and neuropeptide release from C fiber endings are inhibited by the histamine at low-concentration interaction with H3-receptors (H3-R), and probably reflects a local feedback circuit between C-fiber nerve endings and mast cells, which control neurogenic inflammation (Dimitriadou V, 1994) (Arrang J-M, 1983) (Arrang J-M G. M.-C., 1987) (Placeholder21). Guerrero, et al. proposed that the administration of low doses of histamine, to achieve and maintain low-circulating concentrations, may lead to a selective interaction of histamine with H3-R. Histamine could constitute a new therapeutic drug in migraine prophylaxis that acts by limiting the excessive inflammatory response involved in migraine pathophysiology.