Hyposerotonin-induced nitric oxide supersensitivity of trigeminovascular system in rat : a hypothetic mechanism of migraine pathogenesis

Abstract

Ample evidences indicate that altered control of craniovascular nociceptive system is an important step in migraine pathogenesis. Recently, it has been shown that migraine patients are supersensitive to infusion of nitric oxide (NO) donating agent. Based on this finding, the hypothesis of "NO supersensitivity" as a cause of migraine headache has been proposed. However, the exact mechanism of such supersensitivity is still a question. Serotonin (5-HT) has been accepted to play a pivotal role in migraine pathogenesis. Changes in this neurotransmitter level were demonstrated to correlate with the attack of migraine. The present study was conducted to investigate relationship between hyposerotonin and cranial microvascular responses to NO as well as its effect on activation of craniovascular nociceptive system. In this study, adult male Wistar rats were divided into control and hyposerotonin groups. Hyposerotonin state was induced by intraperitoneal injection with 300 mg/kg of para-chlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor, three days before the experiment. After 5-HT depleting procedure, animals were prepared for assessment of NO-induced vasomotor response using nitroglycerin (NTG: 8 and 10 mg/kg, i.v.) as a NO-donor. Pial microcirculation was visualized by intravital fluorescein videomicroscopic technique. Images of vessels at 0, 5, 15, 30 and 60 minutes post NTG-infusion were digitized and measured. At the end of monitoring, rat brains were removed for ultrastructural study of cerebral microvessels by electron microscopy. Fos immunoreactivity, as studied by immunohistochemistry, was used as an indicator of effects of NO exposure on craniovascular nociceptive system. The results showed that infusion of NTG produced dose-dependent pial arteriolar dilatation. This vasodilator effect was significantly increased in PCPA-treated groups, especially at 30 and 60 minutes. Per cent change from baseline diameter at 30 minute after 8 mg/kg NTG infusion were 42.5+-3.1 and 16.8+-2.7 for hyposerotonin and control groups, respectively (P<0.001). Electron microscopic study revealed that exposure to NO donor produced considerable changes in cerebral microvessels, characterizing by increased microvillous formation, increased endothelial pinocytosis, swelling of endothelial mitochondria, focal swelling of endothelial cells and swelling of perivascular astrocytic footplate causing partial separation of microvessels from adjacent brain tissue. These anatomical changes were significantly more prominent in hyposerotonin group. Exposure to NO donor (NTG 10 mg/kg) also activates Fos immunoreactivity in various brain areas, mostly related to nociceptive information processing. Fos immunoreactivity can be demonstrated in trigeminal nucleus caudalis, lateral reticular nucleus, nucleus tractus solitarius, inferior olive, paraventricular nucleus of hypothalamus and habenular of epithalamus. However, the numbers of Fos positie neurons in control and hyposerotonin groups were not different. The above data indicate that (1) exposure to NO can induce substantial changes in pial and cerebral microvessels as well as can activate the craniovascular nociceptive pathway; and (2) hyposerotonergic conditon can facilitate the NO-induced physiological and pathological responses in pial and cerebral microvessels. These observations raise the possibility of hyposerotonin as a cause of NO supersensitivity observed in migraine patients.