Raising Money for
Migraine Research

2017 MRF Research Grantee
FINAL REPORT: OXYTOCIN RECEPTORS ON SHENOPALATINE GANGLIA NEURONS
Summary
The sphenopalatine parasympathetic ganglia (SPG) sits just below the nasal mucosa and is the target for some headache therapies, including topical application (to the mucosa) of local anesthetics and electrode implants. The SPG provides parasympathetic innervation not only of the tissues, but also of the vasculature of the meninges. These fibers release pituitary adenylate cyclase activating polypeptide-38 (PACAP-38) onto the arterioles, bringing multiple inflammatory mediators into the surrounding tissue. As a result, PACAP-38 appears to be critical in the pathogenesis of at least some kinds of headache and has become a target for therapeutic development.
Pain information associated with headache is transmitted to the central nervous system via the trigeminal nerve. We have previously shown that nasally-applied oxytocin can act at oxytocin receptors (OTXR) on trigeminal neurons to inhibit their firing, block their release of calcitonin gene related peptide (CGRP) and profoundly inhibit craniofacial pain in rats and headache in patients. This project investigated whether oxytocin receptors were also on SPG neurons. We found that oxytocin receptors are on SPG neurons, that oxytocin can inhibit the firing of SPG neurons, and that oxytocin can, in vitro, reduce the dural release of PACAP-38.
Hypothesis vs. Findings
This project involved three hypotheses:
Hypothesis 1: that OTXR will be present on most SPG neurons and that many of these neurons will also express the parasympathetic transmitter PACAP-38. We found that a) oxytocin receptors were, in fact, present on SPG neurons and b) that the majority of these neurons also co-expressed PACAP-38.
Hypothesis 2: that exposure of rat SPG neurons, in vitro, to oxytocin will decrease their excitability.
Early data strongly supported the contention that oxytocin can functionally inhibit the firing of SPG neurons and so decrease their excitability. However, subsequent experiments were unable to replicate this result. This may be due, in part, to the inherent difficulty in isolating and maintaining these SPG cells. More work must be done to replicate this data.
Hypothesis 3: that oxytocin exposure of rat meninges, which are one of the sites of termination of SPG neurons and where SPG release of PACAP-38 likely participates in the pathogenesis of some headaches, will decrease the release of PACAP. We found that there is a measurable base level of PACAP-38 from SPG neuronal terminals and that the addition of oxytocin substantially reduces this level. These data suggest that SPG neurons produce an ongoing level of PACAP-38 release – maintaining a parasympathetic tone to meningeal arterioles, and that oxytocin can decrease that release. As a result, oxytocin could be useful in decreasing parasympathetically-mediated headache and other symptoms.
Unanswered Questions
PACAP-38 released from activated SPG neurons appears to be critical in the genesis of parasympathetic symptoms associated with migraine and other headaches. This release in the meninges may play an important role in the pathogenesis of some of these headaches. We have shown that oxytocin receptors are located on PACAP-38 expressing rat SPG neurons, that oxytocin can, in some experiments, decrease their excitability and their release of PACAP-38. However, assuming that this inhibition is replicable, more work is needed to determine whether it can lead to a decrease in pain and parasympathetic symptoms in rat models. And, as this has only been studied in rats, it is also unknown whether these findings would be translatable to humans.
What this Research Means to You
As we have previously shown that nasally-applied oxytocin concentrates in the trigeminal nerve which innervates the nasal mucosa, it is possible that it also concentrates in the SPG, which also innervates the nasal mucosa. If this is the case, then nasal application of oxytocin may be effective in decreasing parasympathetic symptoms of migraine and potentially decrease migraine pain.