Oxytocin as a regulatory neuropeptide in the trigeminovascular system: Localization, expression and function of oxytocin and oxytocin receptors

Abstract

Background Recent clinical findings suggest that oxytocin could be a novel treatment for migraine. However, little is known about the role of this neuropeptide/hormone and its receptor in the trigeminovascular pathway. Here we determine expression, localization, and function of oxytocin and oxytocin receptors in rat trigeminal ganglia and targets of peripheral (dura mater and cranial arteries) and central (trigeminal nucleus caudalis) afferents. Methods The methods include immunohistochemistry, messenger RNA measurements, quantitative PCR, release of calcitonin gene-related peptide and myography of arterial segments. Results Oxytocin receptor mRNA was expressed in rat trigeminal ganglia and the receptor protein was localized in numerous small to medium-sized neurons and thick axons characteristic of A∂ sensory fibers. Double immunohistochemistry revealed only a small number of neurons expressing both oxytocin receptors and calcitonin gene-related peptide. In contrast, double immunostaining showed expression of the calcitonin gene-related peptide receptor component receptor activity-modifying protein 1 and oxytocin receptors in 23% of the small cells and in 47% of the medium-sized cells. Oxytocin immunofluorescence was observed only in trigeminal ganglia satellite glial cells. Oxytocin mRNA was below detection limit in the trigeminal ganglia. The trigeminal nucleus caudalis expressed mRNA for both oxytocin and its receptor. K+-evoked calcitonin gene-related peptide release from either isolated trigeminal ganglia or dura mater and it was not significantly affected by oxytocin (10 µM). Oxytocin directly constricted cranial arteries ex vivo (pEC50 ∼ 7); however, these effects were inhibited by the vasopressin V1A antagonist SR49059. Conclusion Oxytocin receptors are extensively expressed throughout the rat trigeminovascular system and in particular in trigeminal ganglia A∂ neurons and fibers, but no functional oxytocin receptors were demonstrated in the dura and cranial arteries. Thus, circulating oxytocin may act on oxytocin receptors in the trigeminal ganglia to affect nociception transmission. These effects may help explain hormonal influences in migraine and offer a novel way for treatment.

A new hypothesis linking oxytocin to menstrual migraine

“…In humans and animals, OT and OTR expression have been demonstrated in the TG and the brain 19,20,40,46,55 . Immunoreactivity of OT and OTR protein expression was significantly localized to calcitonin gene‐related peptide (CGRP) positive and myelinated Aδ sensory neurons and fibers in the TG as well as in trigeminal satellite glial cells 20,56 56 .…”

“…19,20,40,46,55 Immunoreactivity of OT and OTR protein expression was significantly localized to calcitonin gene-related peptide (CGRP) positive and myelinated Aδ sensory neurons and fibers in the TG as well as in trigeminal satellite glial cells. 20,56 The CNS OTR has been demonstrated in areas known to be critical to migraine pathogenesis. 56 Distribution of [ 125 I]-OT using tissue counts and autoradiography after intranasal administration to rodents showed strong localization of OT label in the TG and in all three branches of the trigeminal nerve as well as in brain regions known to be rich in OTR, 20 including areas of the CNS associated with migraine, including the pons, medulla (particularly the dorsal horn of nucleus caudalis), hippocampus, thalamus, and midbrain.…”

Identifying New Antimigraine Targets: Lessons from Molecular Biology

“…As the ion channels are downstream of both the CGRP receptor and G i -coupled receptors, they might prove more efficient in blocking the hypersensitivity and pain. In addition, to fully understand the nonresponders, we need to understand factors such as migraine chronification [15] and hormonal influence on migraine pathology [91,92].…”

Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

“…A key question is, however, why does estrogen affect migraine mechanisms in some but not in others? The presence of sex hormone receptors in the TVS suggests that trigeminal neurons are sensitive to variations in the levels of these hormones [21] and some of this could be linked to oxytocin [22].…”