Serotonin in Trigeminal Ganglia of Female Rodents: Relevance to Menstrual Migraine

Abstract

Objectives.-We examined changes in the serotonin system across the estrous cycle in trigeminal ganglia of female rodents to determine which components are present and which are regulated by the variations in levels of ovarian steroids that occur during the estrous cycle.Background.-Migraine is 2-3 times more prevalent in women than in men and attacks are often timed with the menstrual cycle, suggesting a mechanistic link with ovarian steroids. Serotonin has been implicated in the pathogenesis of migraine, and the effectiveness of triptans, selective 5HT-1B/D/F agonists, has provided further support for this concept. It is not known whether serotonin, its rate-limiting enzyme tryptophan hydroxylase (TPH), or its receptors are regulated by ovarian steroids in trigeminal ganglia.Methods.-We used reverse transcription-polymerase chain reaction to examine gene expression in cycling mice, Western blots to examine protein expression, double-labeling immunohistochemistry using markers of nociceptors and nonnociceptors and confocal microscopy to identify specific types of neurons, and primary tissue culture to examine effects of estrogen on trigeminal neurons in vitro.Results.-In C57/BL6 mice mRNA levels of TPH-1, the rate-limiting enzyme in serotonin synthesis, were over 2-fold higher and protein levels were 1.4-fold higher at proestrus, the high estrogen stage of the cycle than at diestrus, the low estrogen stage. TPH protein also was present in primary trigeminal cultures obtained from female SpragueDawley rats, but levels were not affected by 24-hour treatment with physiological levels (10 −9 M) of 17β-estradiol. Gene expression of 5HT-1B and 5HT-1D receptors in trigeminal ganglia was not regulated by the estrous cycle. Serotonin was present in trigeminal neurons containing CGRP, a potent vasoactive neuropeptide, peripherin, an intermediate filament present in neurons with unmyelinated axons, neurofilament H, which is present in neurons with myelinated axons, and in neurons binding IB4, a marker of nonpeptidergic nociceptors. Serotonin was also present in neurons containing 5HT-1B. The serotonin-positive population was significantly larger in diameter than the serotonin-negative population.Conclusions.-Expression of the rate-limiting enzyme required for serotonin synthesis is regulated during the natural estrous cycle, and serotonin is present in larger trigeminal neurons of all the major subtypes. Colocalization of serotonin with 5HT-1B suggests that this receptor functions as an autoreceptor to regulate serotonin release. Cyclical changes in serotonin levels in trigeminal ganglia could contribute to the pathogenesis of menstrual migraine.

Serotonin and CGRP in Migraine

“…40,41 Serotonin vasoconstricts the nerve endings and blood vessels and in this way affects nociceptive pain. 42 Comings 43 postulated that low serotonin levels dilate blood vessels and initiate migraine.…”

“…It has been found that most of the neurons present in the dorsal raphe (site of emergence of trigeminal nerve) and trigeminal ganglia are serotonergic. 10,40,44 Serotonin (5-hydroxytryptamine, 5-HT) synthesis involves the rate limiting enzyme, tryptophan hydroxylase (TPH) 45 and is mainly degraded by the action of monoamine oxidases. 46 Tryptophan hydroxylase activity in rat brain base arteries has been suggested to be a marker of serotonergic innervations.…”

Menstrual migraine: a clinical review

“…Limited data imply that this may have a genetic basis. 58 It has been suggested that when estrogen levels peak, increased neuronal excitability is balanced by homeostatic gene regulation in the brain cortex and nociceptive systems. As levels fall around menstruation, a mismatch in homeostatic gene regulation by estrogen unmasks non-nuclear mitogenactivated hyperexcitability of cell membranes, sensitising neurons to triggers that activate migraine attacks.…”

Influence of Gender Difference in the Antidepressant Effect of Fluoxetine in Mice in Tail Suspension Test

“…Furthermore, the administration of estrogen upregulates 5-HT synthesizing enzyme, i.e. tryptophan hydroxylase [55,56], downregulates SERT upon shortterm treatment [57], whereas upregulates SERT following long-term treatment [58], decreases the expressions of 5-HT metabolizing enzyme, i.e., monoamine oxidase [59], and reduces the expression of 5-HT 1A receptor in the various regions of brain [60,61]. Therefore, estrogen modulates both the density of 5-HT receptors and 5-HT turnover [62,63].…”