5‐HT_1D Receptor Immunoreactivity in the Sphenopalatine Ganglion: Implications for the Efficacy of Triptans in the Treatment of Autonomic Signs Associated With Cluster Headache

Abstract

Objective To determine if 5-HT1D receptors are located in the sphenopalatine ganglion. Background While the 5-HT1D receptor has been described in sensory and sympathetic ganglia in the head, it was not known whether they were also located in parasympathetic ganglia. Methods We used retrograde labeling combined with immunohistochemistry to examine 5-HT1D receptor immunoreactivity in rat sphenopalatine ganglion neurons that project to the lacrimal gland, nasal mucosa, cerebral vasculature and trigeminal ganglion. Results We found 5-HT1D receptor immunoreactivity in nerve terminals around postganglionic cell bodies within the sphenopalatine ganglion. All 5-HT1D immunoreactive terminals were also immunoreactive for calcitonin-gene related peptide but not vesicular acetylcholine transporter, suggesting that they were sensory and not preganglionic parasympathetic fibers. Our retrograde labeling studies showed that approximately 30% of sphenopalatine ganglion neurons innervating the lacrimal gland, 23% innervating the nasal mucosa and 39% innervating the trigeminal ganglion were in apparent contact with 5-HT1D receptor containing nerve terminals. Conclusion These data suggest that 5-HT1D receptors within primary afferent neurons that innervate the sphenopalatine ganglion are in a position to modulate the excitability of postganglionic parasympathetic neurons that innervate the lacrimal gland and nasal mucosa, as well as the trigeminal ganglion. This has implications for triptan (5-HT1D receptor agonist) actions on parasympathetic symptoms in cluster headache.

AVP‐825 Breath‐Powered Intranasal Delivery System Containing 22 mg Sumatriptan Powder vs 100 mg Oral Sumatriptan in the Acute Treatment of Migraines (The COMPASS Study): A Comparative Randomized Clinical Trial Across Multiple Attacks

“…9,10 The early migraine efficacy observed with AVP-825 at a lower dose than the 100 mg oral sumatriptan may reflect quick systemic absorption of sumatriptan powder when delivered by the bi-directional breath-powered delivery system to the highly absorptive upper posterior surfaces of the nasal cavity and to cranial nerve structures potentially relevant for migraine therapy. 5,8 Other factors potentially contributing to early onset of effect with this unique intranasal form of delivery at the lower dose include possible serotonergic action at nerve endings in the nasal cavity 5,9,28 or direct delivery to the brain (via olfactory or trigeminal nerves), but no direct evidence for these mechanisms has been established. 7,29 The results of COMPASS indicate that the main difference in efficacy between AVP-825 and 100 mg oral sumatriptan occurs early, within 2 hours postdose, likely due in large part to faster sumatriptan absorption with AVP-825.…”

The Nasal Approach to Delivering Treatment for Brain Diseases: An Anatomic, Physiologic, and Delivery Technology Overview

“…In addition, the maxillary branch of the trigeminal nerve innervating the remainder of the respiratory nasal mucosa offers a potential route for drug transport to the regions of the brainstem where these nerves fiber project [26,27]. Transport may also occur along the parasympathetic fibers of the trigeminal nerve accompanying the sensory nerves to the sphenopalatine ganglion ( Figure 1) [70,71]. The clinical observations suggesting CNS effects of macromolecules such as insulin and oxytocin delivered with conventional spray pumps may in fact be attributable primarily to this trigeminal pathway [45,46,72].…”

A Novel Translational Animal Model of Trigeminal Autonomic Cephalalgias

“…The data show that while both were effective at inhibiting SuS‐evoked firing, the use of a triptan was significantly more effective than the CGRP receptor antagonist . The significant response of both treatments might be expected as they are known to act on central trigeminovascular neurons, but the disparity of response with the triptan would seem to indicate that it may be acting on additional sites, most likely the parasympathetic outflow to the cranium, where it is known 5‐HT 1D receptors are present . Finally, the effects of the COX inhibitors indomethacin and naproxen were characterized in both dural and SuS‐evoked assays.…”

“…Dural-evoked TCC firing SuS-evoked TCC firing 13,14 SuS-evoked lacrimal gland/ duct flow 13,14 Triptans 51-69% inhibition 38,42 63-70% inhibition 56 might be expected as they are known to act on central trigeminovascular neurons, but the disparity of response with the triptan would seem to indicate that it may be acting on additional sites, most likely the parasympathetic outflow to the cranium, where it is known 5-HT1D receptors are present. 52 Finally, the effects of the COX inhibitors indomethacin and naproxen were characterized in both dural and SuS-evoked assays. An indomethacin response defines the diagnosis of paroxysmal hemicrania and hemicrania continua while other COX inhibitors are relatively ineffective, 53 whereas naproxen is reliably used in the treatment of migraine.…”