Effect of Sex and Estrogens on Neuronal Activation in an Animal Model of Migraine

Headache: The Journal of Head and Face Pain

Article first published online: 22 AUG 2012

DOI: 10.1111/j.1526-4610.2012.02249.x

1. Rosaria Greco PhD^*, 
2. Cristina Tassorelli MD, 
3. A. Stefania Mangione PhD, 
4. Antonella Smeraldi PhD, 
5. Marta Allena MD, 
6. Giorgio Sandrini MD, 
7. Giuseppe Nappi MD, 
8. Rossella E. Nappi MD

Objective.— In this study, we evaluated the influence of sex and estrogen treatment on nitroglycerin (NTG)-
induced neuronal activation in the rat brain.

Background.— Systemic NTG activates cerebral nuclei of rat involved in nociceptive transmission, as well as in neuroendocrine and autonomic functions. These changes are considered relevant for migraine, since NTG consistently induces spontaneous-like attacks in migraineurs.

Methods.— Intact and castrated male and female rats, and castrated female rats treated with estradiol benzoate (or placebo) were injected with NTG and sacrificed after 4 hours. Rats were perfused, and their brains were processed for Fos protein, a marker of neuronal activation.

Results.— Data showed a reduced expression of NTG-induced Fos protein in the paraventricular nucleus (PVH), supraoptic nucleus (SON), and nucleus trigeminalis caudalis (SPVC) of male rats in comparison with female rats. Furthermore, in castrated female rats, NTG-induced neuronal activation was reduced in PVH, SON, central nucleus of the amygdala (AMI), nucleus tractus solitarius (NTS), area postrema (AP), and SPVC, while in castrated male rats Fos expression was reduced uniquely in the SPVC. Chronic administration of estrogens restored Fos protein expression in PVH, SON, AMI, NTS, AP, and SPVC in castrated female rats.

Conclusion.— These data provide a support for the existence of a sexual dimorphism in NTG-induced neuronal activation, and they prompt a specific model for evaluating and modulating the influence of estrogens upon the cerebral structures implicated in the pathophysiology of migraine.

Delayed migraine-like headache in healthy volunteers after a combination of acetazolamide and glyceryl trinitrate

Cephalalgia

Volume 29 Issue 12, Pages 1294 - 1300

Published Online: 11 May 2009

© 2008 International Headache Society

D Daugaard, LL Thomsen, HK Iversen & J Olesen

Department of Neurology, Glostrup Hospital, University of Copenhagen, Glostrup, Copenhagen, Denmark

Correspondence to Jes Olesen MD, PhD, Department of Neurology, Glostrup Hospital, Nordre Ringvej, Glostrup, 2600 Denmark. Tel. + 45-4323-3036, e-mail jeol@glo.regionh.dk

ABSTRACT

Glyceryl trinitrate (GTN) is a pro-drug dissociating nitric oxide throughout the body. It dilates cephalic arteries without increasing cerebral blood flow (CBF). GTN induces headache in healthy volunteers and migraine attacks in migraineurs. Acetazolamide (Az) increases CBF but does not dilate cerebral arteries. The hypothesis tested here was that Az, by dilating cerebral arterioles but not arteries and thereby decreasing pulsatile stretching of the wall of the large arteries and their perivascular sensory nerves, would reduce or prevent the GTN-induced headache We tested this hypothesis in 14 healthy volunteers. In a randomized, double-blind, cross-over study, they were pretreated with Az or placebo followed on both study days by a GTN infusion of 0.5 µg kg⁻¹ min⁻¹ for 20 min. Headache was scored on a verbal rating scale and a headache diary was kept for 12 h. Mean blood velocity of the middle cerebral artery was measured (transcranial Doppler). Our hypothesis was disproved, as Az did not decrease GTN-induced headache. Unexpectedly but interestingly, GTN combined with Az induced more delayed headache than GTN alone. Furthermore, a migraine-like headache was observed in three volunteers, who did not develop migraine after GTN alone. The fact that a suitable pharmacological intervention may trigger migraine in individuals with no prior migraine may suggest that the ability to develop migraine without aura is a quantitative genetic trait.

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Received 18 December 2008, accepted 15 February 2009