Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal.

The maxillary sinus is frequently implicated in facial pain syndromes arising from infection, neoplasia, dental procedures, and, importantly, migraine, which can mimic “sinus headache” and contribute to misdiagnosis and inappropriate antibiotic use. Despite the clinical burden of chronic maxillary sinus pain, the sensory neuron subtypes that convey nociceptive and mechanosensory signals from the sinus mucosa remain incompletely defined. In this study, trigeminal ganglion (TG) neurons innervating the maxillary sinus (sinus TG neurons) were retrogradely labeled with DiD in mice and characterized using ex vivo patch-clamp electrophysiology and single-cell RT-PCR. Sinus TG neurons were found to be predominantly small-diameter, C-afferent nociceptors with electrophysiologic features including high thresholds, repetitive firing, and broad action potentials. Notably, sinus TG neurons formed a distinct molecular and functional subgroup: they expressed Nav1.9, while showing minimal Nav1.8 expression and limited overlap with Nav1.8-positive nociceptor populations. A majority of sinus TG neurons were mechanically responsive, generating mechanically activated currents with heterogeneous adaptation profiles, and a subset expressed the mechanoreceptor Piezo2. Collectively, these findings identify sinus TG neurons as a specialized population of Nav1.9-enriched C-afferent nociceptors with mechanosensitive properties, providing a mechanistic framework for pressure-evoked sinus pain. This work advances the neurobiological basis of sinus-related pain and suggests that Nav1.9 and mechanoreceptor pathways may be potential therapeutic targets for conditions in which sinus symptoms overlap with migraine and other craniofacial pain disorders.

The maxillary sinus is frequently implicated in facial pain syndromes arising from infection, neoplasia, dental procedures, and, importantly, migraine, which can mimic “sinus headache” and contribute to misdiagnosis and inappropriate antibiotic use. Despite the clinical burden of chronic maxillary sinus pain, the sensory neuron subtypes that convey nociceptive and mechanosensory signals from the sinus mucosa remain incompletely defined. In this study, trigeminal ganglion (TG) neurons innervating the maxillary sinus (maxillary sinus TG neurons) were retrogradely labeled with the fluorescent dye DiD in mice and characterized using ex vivo patch-clamp electrophysiology and single-cell RT-PCR. Maxillary sinus TG neurons were found to be predominantly small-diameter, C-afferent nociceptors with electrophysiologic features including high thresholds, repetitive firing, and broad action potentials. Notably, maxillary sinus TG neurons formed a distinct molecular and functional subgroup: they expressed Nav1.9, while showing minimal Nav1.8 expression and limited overlap with Nav1.8-positive nociceptor populations. A majority of maxillary sinus TG neurons were mechanically responsive, generating mechanically activated currents with heterogeneous adaptation profiles, and a subset expressed the mechanoreceptor Piezo2. Collectively, these findings identify maxillary sinus TG neurons as a specialized population of Nav1.9-enriched C-afferent nociceptors with mechanosensitive properties, providing a mechanistic framework for pressure-evoked sinus pain. This work advances the neurobiological basis of sinus-related pain and suggests that Nav1.9 and mechanoreceptor pathways may be potential therapeutic targets for conditions in which sinus symptoms overlap with migraine and other craniofacial pain disorders.