Throbbing pain suggests an origin in arteries, and it has been known for many years that meningeal and large cerebral arteries are capable of transmitting painful sensations. Thus, studies of migraine pathogenesis have focused on meninges and meningeal vessels, and it is thought that migraine involves meningeal inflammation (95). There are at least four potential mechanisms whereby ovarian steroids could modulate meningeal inflammation. First, meningeal vessels are a potential site of estrogen effects, as they express estrogen receptor-α, which increases after estrogen treatment (129). Second, hormones may alter responses of meningeal mast cells. Estrogen receptors in dural mast cells modulate histamine release (109), and histamine excites nociceptive terminals. Third, estrogen may modulate expression of proinflammatory cytokines by macrophages present on the meningeal linings of the subarachnoid space (87) and in the dura, where they are aligned along blood vessels, especially near the superior sagittal sinus (85). Proinflammatory cytokines also excite nociceptive terminals (153). Estrogen modulates expression of proinflammatory cytokines in macrophages (68) and reduces leukocyte migration into injured vessels (153). Fourth, ovarian steroids may regulate sensory sensitization by modulating expression of nerve growth factor (NGF). Retrograde transport of receptor-bound NGF stimulates synthesis of CGRP, substance P, and PACAP (71,72,96). Blocking the high-affinity NGF receptor trkA prevents sensory sensitization following inflammation (14,64). Dural tissue expresses NGF (134), and estrogen treatment alters NGF expression in some tissues (16). Effects of NGF on meninges are unknown.

The trigeminal ganglion contains several populations of neurons (see review by Lazarov [69]) that express neuropeptides such as substance P and CGRP, but also other peptides potentially relevant to migraine including PACAP, atrial natiuretic peptide, neurokinin A, endothelin-1, enkephalin, dynorphin cholecystokinin, bombesin, somatostatin, vasoactive intestinal peptide, and galanin (see review by Lazarov [69]). Trigeminal neurons express ERα, which is likely to regulate expression of many of these peptides.

Progesterone receptors are present in dorsal root ganglia (DRG) of female rats. Ovariectomy reduces expression of these receptors and increases behavioral
hypersensitivity to heat (93), suggesting a link between low progesterone levels and increased pain sensitivity. Progesterone may also regulate trigeminal function indirectly via effects on CGRP and the NGF-trkA system (41). Very little information is available about the potential role of progesterone or its receptors in trigeminal neurons.

Numerous studies have shown that phenotypic changes in sensory neurons accompany changes in response to painful stimuli from temporary to severe and chronic. Cutaneous allodynia occurs in certain well-defined regions of the skin during migraine, suggesting hyperexcitability of pain pathways (22), and migraineurs have significantly lower thresholds for the blink reflex and an increased sensitivity to tactile and painful stimuli, even during the interictal period (115). These increased responses indicate sensitization of trigeminal neurons.

Phenotypic plasticity of nociceptive sensory neurons is regulated by the NGF-trkA system (88). Small DRG neurons that are positive for CGRP transport NGF from the periphery (1,152). During inflammation, NGF levels increase (110) resulting in inflammatory hyperalgesia (84,150, 151,152). Inflammation of orofacial tissue results in increased CGRP and substance P in the trigeminal ganglion (53). In addition, motifs that mimic a classical estrogen response element are found in the promoter and 5′-flanking regions of the genes for human trkA (125,135).

Sensory sensitization is associated with altered expression of neuropeptides (NP) such as NPY and galanin in trigeminal neurons in males (35,40). In females, NPY and galanin are regulated by ovarian steroids. NPY is a vasoconstrictive peptide usually associated with the parasympathetic nervous system. NPY-immunoreactive nerve fibers and receptors are expressed around cerebral vessels (12), and NPY inhibits dural plasma protein extravasation after trigeminal stimulation (155). Increased levels of NPY are present in cerebral spinal fluid after a migraine attack (139). Both Y1 and Y2 NPY receptors are located in trigeminal ganglia (131). NPY mRNA levels vary with the phase of the estrous cycle in female mice, with highest levels present at early estrus (104). Galanin increases markedly after nerve injury (49), when it regulates nociceptive signaling (50,62,63,75). In male mice, injury increases the galanin content of dorsal root ganglion cells 120-fold and the number of galanin positive neurons increases from 5% to more than 50% (2). Galanin injections into inflamed knee joints in rats cause a significant reduction in responses to noxious movements, suggesting that galanin is a critical component of the tonic inhibitory system for inflammatory pain (47). In the pituitary, estrogen upregulates galanin mRNA expression up to 4000-fold and immunoreactivity up to 50-fold (59). In mice, galanin expression in trigeminal neurons is highest at proestrus, the stage of the estrous cycle when estrogen levels are highest (104). Galanin has several G-protein-coupled receptors including GalR1, GalR2, and GalR3 (20). GalR1, which has antinociceptive functions (52,61,74), is expressed in trigeminal ganglia and in peripheral targets of trigeminal neurons (130). GalR1 expression in the hypothalamus is modulated by ovarian steroids and is highest at proestrus (37). It is not known if ovarian steroids regulate GalR1 expression in the trigeminal system.

The information regarding the peripheral action of sex hormones has been obtained from experimental animals. This is because there are no noninvasive techniques that can provide this type of information using human subjects. More data on the role of sex hormones in the
central processing of trigeminal pain processing in human are known because of the advances in imaging techniques. The currently available information from human studies correlates well with the animal studies of the role of sex hormones.

Information related to activation of sensory terminals innervating the dura and meninges are transmitted to neurons within the nucleus caudalis of the trigeminal complex. Functionally, this region, and its caudal extent into the cervical spinal cord, integrate nociceptive information arriving from the periphery and the descending systems and transmits this information to the medullary, pontine thalamic, and hypothalamic regions (11,26,118). Anatomic studies using injection of retrograde tracers into the TNC have identified four major sites as targets of TNC projections (26,32,46,78, 79, 80,94,99,107,108,119,148). These sites are the periaqueductal gray (PAG), the parabrachial nucleus (PBN), medial preoptic nucleus of the hypothalamus, and the ventrobasal nucleus of the thalamus. Further, injections of anterograde tracers into each of these sites indicate site-specific afferents from the TNC neurons that in turn receive afferents from the meninges and dura. The sites that receive afferents from TNC contain a dense population of sex hormone receptors and terminals. Therefore, changes in the level of these hormones can modulate signal processing within the TNC and propagation of these signals to the forebrain. The functions related to sex hormones in each of these sites are discussed next.