The distribution of oxytocin and the oxytocin receptor in rat brain: relation to regions active in migraine

DOI: https://doi.org/10.1186/s10194- 020- 1079- 8

Abstract-Summary Recent work, both clinical and experimental, suggests that the hypothalamic hor- mone oxytocin (OT) and its receptor (OTR) may be involved in migraine pathophysiology.

In order to better understand possible central actions of OT in migraine/headache pathogenesis, we mapped the distribution of OT and OTR in nerve cells and fibers in rat brain with a focus on areas related to migraine attacks and/or shown previ- ously to contain calcitonin gene related peptide (CGRP), another neuropeptide involved in migraine.

OT also was found in many other regions of the brain where it was localized

mainly in nerve fibers.

OTR staining in the brain was mainly observed in cell somas with very little

expression in fibers.

In some regions of the brain (e.g. the amygdala and the hypothalamus), both OT

and OTR were expressed (match).

2.5 Hormones

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Mismatch between the peptide and its receptor was primarily observed in the cerebral and cerebellar cortex (OT expression) and hippocampus (OTR expression). We compared OT/OTR distribution in the CNS with that of CGRP and identified

regions related to migraine.

Introduction Some OT is released from centrally projecting parvocellular neurons of the Pa. These contain however much less peptide levels than do the magnocellular neu- rons [724].

The magnocellular neurons of SO and Pa project to the posterior pituitary gland where they release OT into the bloodstream thus controlling endocrine events asso- ciated with reproduction in both males and females [725].

OT is released from the cell bodies and dendrites of these neurons [726]. In males, and females, OT neurons are continuously active. The aim of the present study was to comprehensively map the distribution of OT and OTR in the male rat brain in order to provide an qualitative overview of their localization in fibres and cells to add to the discussion of migraine/headache patho- genesis in general and to compare with their localization with that of calcitonin gene-related peptide (CGRP) and CGRP receptors in the brain [727].

Materials and Methods The 6th edition of The Rat Brain in Stereotaxic Coordinates by Paxinos and Watson [728] and HE staining of sagittal sections spanning over 0.5 mm to 1.5 mm lateral to the midline were used to identify the different areas subjected to the detailed study of OT and OTR distribution.

Sagittal cryo-sections of the whole brain, including cerebellum, brain stem and C1 spinal cord were stained using Hematoxylin and Eosin (Htx 4 min, Eosin 1 min). The staining was done in order to examine the morphology and condition of the

tissue, and to identify the distance of the section of the brain from the midline.

As regards to OTR antibodies, anti-goat oxytocin receptor ab87312 from Abcam and anti-rabbit oxytocin receptor AVR-013 from Alomone also showed consistent and comparable results, and were therefore used in the present study.

Results Consistent with this view, OT immunoreactivity observed in other parts of the brain was found mainly in fiber structures but not cell somas.

Some OT immunoreactive cells were found in the lateral reticular nucleus (LRt)

and Sp5.

In the reticular formation, a few cells—the lateral reticular nucleus (LRt)—were

found to express OT.

These few cells are the only cells in addition to SO, Pa and Sp5 (and TNC, see

above) that were OT immunoreactive in the brain.

To OT immunohistochemistry, OTR staining was mainly found in cell somas

with very little observed in fibers.

Both the amygdala and the hypothalamus were regions where OT and OTR

expressions were observed.

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2 Mechanisms

We compared these regions with the expression of OT and OTR, and found con- gruent distribution in cerebral cortex and cerebellum, pons, amygdala, hypothala- mus and Sp5 region.

Discussion We demonstrate that OT and OTR are present in a number of brain regions associ- ated with migraine, thus strengthening our insight into possible involvement of OT in migraine attacks.

A central role of OT is that both OT and vasopressin are released within the brain by centrally projecting parvocellular neurons (fibers) and also from the soma and dendrites of magnocellular neurons [724, 729, 730].

It has been shown that magnocellular OT neurons project to more than 50 fore- brain regions, in addition to their well-known terminations in the posterior pituitary. We demonstrate using immunohistochemistry a delicate network of fibers expressing OT in many areas of the rat brain, however, the positive fibers in the cerebral cortex showed the most remarkably stunning organization, resembling the distribution of CGRP receptors [727].

When comparing migraine active regions seen in imaging studies of migraine patients [731] and the localization of OT/OTR, it shows that there is overlap in sev- eral parts of the brain.

Conclusion The current study examined the CNS distribution of OT and its receptor with a focus on migraine-related regions and areas expressing CGRP/receptors.

Acknowledgement A machine generated summary based on the work of Warfvinge, Karin; Krause, Diana; Edvinsson, Lars. 2020 in The Journal of Headache and Pain

Clinical symptoms of androgen deficiency in men with migraine or cluster headache: a cross-sectional cohort study