The Involvement of Trigeminal Substance P Neurons in Cluster Headache. An Hypothesis

Abstract

SYNOPSIS Substance P (SP) neurons, with bipolar axons from the cell body, in sensory ganglia, exhibit unique properties in that impulses may travel either orthodromically or antidromically in the various ramifications of the axons, and that the transmitter may be released both in the central and peripheral ends of the neuron. Thus, these nerves are not only sensory, carrying nociceptive impulses from the periphery, but also motor with ability to dilate blood vessels, constrict smooth muscle cells and cause protein extravasation, glandular secretion, release from mast cells and excitation of autonomic ganglion cells. Within the individual neuron several local reflex arches ‐ axon reflexes ‐ are established in this way. An hypothesis is forwarded about the pathophysiology of cluster headache, against the background of recent morphological and functional evidence for SP neurons in the ipsilateral trigeminal nerve and its connections to various cranial structures including the sphenopalatine (pterygopalatine) ganglion and internal carotid perivascular nerve plexus. Activation of SP fibers in the ophthalmic and maxillary divisions may give rise to practically all symptoms of an attack of cluster headache. This provides a rational explanation for the beneficial effect on both pain and vegetative symptoms achieved by blockade of the Gasserian or sphenopalatine ganglia in this disease. A temporary arrest of central inhibitory serotonergic impulses presynaptically on the SP neurons in the caudal trigeminal nucleus is, with our present knowledge, a likely explanation for such an activation, even if it may not be the only factor. A comparison is made with the present opinion on activation of parasympathetic and blockade of sympathetic nerves to explain the various symptoms of a cluster attack.

Origins and Pathways of Cerebrovascular Vasoactive Intestinal Polypeptide-Positive Nerves in Rat

“…Against the background of the strong vasodilatory capacity of VIP and the strategic location of the VIP ganglion cells at the entrance of vessels to the cerebral vas cular bed through the skull base, Gibbins et al (1984) speculated that the VIP nerves are activated under conditions of heat stress. One clinical impli cation for a local vasodilatory capacity of the in ternal carotid artery in the carotid canal upon acti vation of the seventh cranial nerve is cluster head ache, in which the internal carotid artery is swollen and dilated at this level during the attacks (Ekbom and Greitz, 1970; see also Hardebo, 1984).…”

The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater

“…Neurogenic inflammation (vasodilatation and plasma protein extravasation) within cephalic tissues has been proposed as a possible mechanism in headache pathogenesis (Moskowitz et at., 1979;Mayberg et al, 1981; Moskowitz, 1984;Hardebo, 1984). Neurogenic inflammation is mediated by release of vasoactive neuropeptides, substance P (SP) (Lembeck & Holzer, 1979), neurokinin A (NKA) and calcitonin generelated peptide (CGRP), from sensory fibres innervating blood vessels (Saria et al, 1985;1986).…”

Further characterization of the putative 5‐HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater

“…In the dura mater there is ultrastrucNeurogenic inflammation (vasodilatation and plasma protein tural evidence for mast cell degranulation, platelet accumulaextravasation) may be important to the pathophysiology of tion, and increase in the number of endothelial vesicles migraine headaches and to the action of antimigraine drugs specifically in postcapillary venules following electrical stimu- (Chapman et al, 1961;Dalessio, 1974;Moskowitz et al, 1979;lation Dimitriadou et al, 1990). Protein Fozard, 1982;Hardebo, 1984; Moskowitz, 1984; al., leakage does not develop in the dura mater after pretreatment 1988). Neurogenic plasma extravasation develops in dura with clinically relevant doses of the antimigraine drugs mater and extracranial cephalic tissues following electrical trisumatriptan, and the ergot alkaloids ergotamine tartrate, geminal stimulation or systemic capsaicin administration and dihydroergotamine and chronic methysergide (Saito et al, can be detected by leakage of albumin tracer (Markowitz et 1988; .…”