Role of nitric oxide in cluster headache

D’Amico, Domenico; Leone, Massimo; Ferraris, A.; Catania, Anna; Carlin, Andrea; Grazzi, Licia; Bussone, Gennaro

doi:10.1007/pl00014993

Cited by 16 publications

(16 citation statements)

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“…Recently, an increase of nitrite levels during the active periods in the peripheral blood of patients with cluster headache has been demonstrated, supporting the involvement of NO in the pathophysiological mechanisms of this primary headache [50].…”

Section: No and Cerebral Spreading Depressionmentioning

confidence: 73%

Nitric oxide in primary headaches

Gallai¹,

Sarchielli²

2000

J Headache Pain

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Nitric oxide (NO) has been proposed to be a key molecule in migraine. Experimental evidence suggests its intervention in vasodilatation and activation of the trigeminovascular system as well as its involvement in the supraspinal pathways implicated in head pain processing. Other findings suggest the implication of NO in coupling neuronal and vascular changes during spreading depression. A potential role for NO has also been proposed in the pathophysiological mechanisms underlying cluster headache and chronic tension-type headache. The most relevant evidence for an increased response to exogenous NO in all primary headaches emerges from the experimental model of nitroglycerin-induced headache. Moreover, the effectiveness of non-selective NO synthase inhibitor L-N-monomethylarginine (L-NMMA) further supports the involvement of NO in migraine and chronic tension-type headache. The endogenous increase in NO production has been shown only in studies carried out during spontaneous migraine attacks which demonstrated increased levels of nitrites and cGMP in peripheral blood and internal jugular blood; the latter was followed by an increased production of algogenic and vasodilatatory prostanoids. These data suggest the potential activation of cyclooxygenase (COX) due to NO. Additional evidence suggests the increased activity of L-arginine/NO pathway in the platelet model in migraine patients. This increase was also evident between attacks, more accentuated during attacks and expressed to a greater extent during late luteal phase in menstrual migraine. Higher NO production in platelet was also demonstrated in patients affected by chronic daily headache and they are accompanied by significant lower serotonin content and higher levels of intracellular calcium. Whether these changes may be expressed in the central nervous system is a matter of discussion. These data taken together suggest a crucial role played by NO in neurovascular headaches and chronic headaches. Further research concerning NO in all primary headaches will be aimed at verifying changes of reliable markers of NO metabolism and NO effects, to better understand the complex COX/NO synthase (NOS) interactions, to investigate the effectiveness of selective NOS inhibitors in discriminating neural versus vascular involvement of NO.

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Section: No and Cerebral Spreading Depressionmentioning

confidence: 73%

Nitric oxide in primary headaches

Gallai¹,

Sarchielli²

2000

J Headache Pain

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“…Nitroglycerin derivatives -as NO donors (NOD) -have been widely used in the past to provoke experimental attacks of both migraine and cluster headache [3,4]. In the last decade the scientific relevance of the NOD experimental model turned on NO ability to activate the endothelial pathways and/or the CNS nuclei by stimulating and/or controlling the following networks: (i) the trigeminovascular system in migraine [5][6][7]; (ii) the hypothalamic area and peripheral endothelial function in cluster headache [8,9]; (iii) the central pain sensitization pathway in chronic tension headache [10]; and (iv) the local release of proinflammatory cytokines in cervicogenic headache, a still debated headache syndrome [11]. Today the molecular role of NO -at both central and peripheral levels -is mainly recognized in migraine [12].…”

Section: Introductionmentioning

confidence: 99%

Expression of NOS–2, COX–2 and Th1/Th2 cytokines in migraine

et al. 2001

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Nitric oxide (NO) probably plays an important role in the pathogenesis of migraine without aura (MWA). As the activation of NO-ergic cascade has been shown to be closely linked to cyclooxygenase pathway and to cause some differences in peripheral blood lymphocyte populations, we investigated if the Th1/Th2 balance in peripheral blood of MWA patients was affected in comparison to controls. Twenty-six MWA patients and 10 healthy controls (C) were enrolled in this study. Blood samples were taken at baseline (T0) and during an induced migraine attack (T1). Total RNA from human peripheral blood lymphocytes (PBLs) was isolated and reverse-transcribed to prepare complementary DNA. COX-2, NOS-2 and β-actin were amplified using PCR. PBLs from patients and controls were stimulated with phorbol 12-myristate 13-acetate plus ionomycin in the presence of brefeldin A. Cells were surfacestained with fluorochrome-conjugated anti-CD3 and anti-CD8 monoclonal antibodies (mAbs) and intracellularly stained with fluorochrome-conjugated anti-IFN-γ or anti-IL-4 mAbs. The level of cytokine expression was analyzed by gating on the CD4 + lymphocyte subset. Th1 and Th2 type cytokines (IFN-γ, IL-2, IL-4) were directly assayed in serum by ELISA. Preliminary results indicate that NOS-2 was upregulated in MWA patients at basal time if compared to controls, whereas after NOD administration NOS-2 was significantly decreased. COX-2 was upregulated in MWA patients at basal time and it had an opposite trend after NOD administration. The homeostatic Th1/Th2 balance defined by the IFN-γ or IL-4 cytokine expression was unchanged in MWA patients in comparison to controls, and NOD administration did not affect that pattern. The cell activation machinery was not altered after mitogenic activation, as shown by CD69 expression level. Cytokine serum levels showed no significant changes in all studied situations. This study confirms the relevance of the NOS/COX system in MWA but, in contrast with previous studies, excludes their effect and activation on peripheral cytokine production. More sophisticated experimental models are needed to investigate the ability of NOS/COX to activate migraine pain.

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“…Migraine pain may originate at the endothelial level via NOS activation [61][62][63][64][65] in connection with activation of the cyclooxygenase pathway [66]. CH may involve, among other mechanisms, NOS activation in the brainstem and at the hypothalamic nuclei level [28,32], with a peripheral NO derangement [67,68]. CEH pain may be the result of a direct pain-producing activity originating from NO itself and proinflammatory cytokines [43].…”

Section: Discussionmentioning

confidence: 99%