Analysis of NOS Gene Polymorphisms in Relation to Cluster Headache and Predisposing Factors in Sweden

Cluster headache is characterized by activation of the autonomic-trigeminal reflex. Nitric oxide can trigger headaches in patients, and nitric oxide signaling is known to be affected in cluster headache. Based on the hypothesis of nitric oxide being involved in cluster headache pathophysiology we investigated nitric oxide synthases as potential candidate genes for cluster headache. We analyzed eight variants in the three forms of nitric oxide synthase (NOS) genes, inducible NOS (iNOS), endothelial NOS (eNOS) and neuronal NOS (nNOS), and tested for association with cluster headache. Swedish cluster headache patients (n = 542) and controls (n = 581) were genotyped using TaqMan® assays on an Applied Biosystems 7500 qPCR cycler. This is the largest performed genetic study on NOS involvement in cluster headache so far. We found an association between cluster headache and one iNOS haplotype consisting of the minor alleles of rs2297518 and rs2779249 (p = 0.022). In addition, one of the analyzed nNOS variants, rs2682826, was associated with reported triptan use (p = 0.039). Our data suggest that genetic variants in NOS genes do not have a strong influence on cluster headache pathophysiology, but that certain combinations of genetic variants in NOS genes may influence the risk of developing the disorder or triptan use.

Sex, blinking, and dry eye

Blinking sustains the corneal tear film generated by sexually dimorphic lacrimal and meibomian glands. Our study examines whether trigeminal control of blinking is also sexually dimorphic by investigating trigeminal reflex blinking, associative blink modification, and spontaneous blinking in male and female rats before and after unilateral dry eye caused by exorbital gland removal. Before gland removal, female rats exhibited a lower threshold for evoking trigeminal reflex blinks, a weaker effect of associative blink modification, and longer-duration spontaneous blinks than males. Spontaneous blink rate, reflex blink excitability, and occurrence of blink oscillations did not differ between the sexes. Reanalysis of previous data showed that humans showed the same blink sexual dimorphisms as rats. During the first 2 wk of dry eye, trigeminal blink circuit excitability and blink oscillations steadily rose in male rats, whereas excitability and blink oscillations did not change in females. Following dry eye, spontaneous blink duration increased for both males and females, whereas spontaneous blink rate remained constant for males but decreased for females. The associative modification treatment to depress trigeminal blink amplitude initially produced blink depression in males that converted to blink potentiation as trigeminal excitability rose, whereas females exhibited progressively more blink depression. These data indicated that dry eye increased excitability in male trigeminal reflex blink circuits at the expense of circuit modifiability, whereas trigeminal modifiability increased in females. This increased modifiability of female trigeminal blink circuits with dry eye may contribute to the preponderance of females developing the focal dystonia, benign essential blepharospasm. NEW & NOTEWORTHY All the elements controlling the corneal tear film are sexually dimorphic. Blinking, which smooths and maintains the tear film, also exhibits sex differences. Dry eye increases the sexual dimorphisms of blinking, including increased exaggeration of excitability in males and enhanced modifiability of the female trigeminal complex. This increased modifiability may explain female predominance in the development of the focal dystonia, benign essential blepharospasm.

Effects of The Remote C Fibres Stimulation Induced by Capsaicin on the Blink Reflex in Chronic Migraine

The aim of this study was to test the function of the diffuse noxious inhibitory control system (DNIC) in chronic and episodic migraine, exploring the blink reflex (BR) modifications induced by topical application of capsaicin on the hand. We evaluated 11 migraine without aura (MA) and nine chronic migraine (CM) patients during the not symptomatic phase; they were compared with 14 non-headache subjects (N). The BR was elicited by weak electrical stimuli delivered to the right supraorbital nerve; it was obtained 10 min and 20 min after the application of 1 ml of 3% capsaicin in a cream base (Teofarma) on the skin of the dorsum of the right hand, and 60 min after capsaicin removal. The subjective pain sensation induced by capsaicin was significantly increased in CM with respect to both MA patients and normal subjects; the R2 area was increased in CM patients during capsaicin application, with respect to controls and MA patients, who did not exhibit any reflex alterations. These results may suggest a failure of DNIC and a disturbed control of the trigeminal reflex at the central level, linked with migraine frequency.