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.