Immunoreactivity of NOS, CGRP, PACAP, SP and VIP in the trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2 of the cat

Abstract

IntroductionNeurovascular headaches, such as migraine and cluster headache, are very disabling, common disorders. Despite much progress in research during recent years both at the therapeutic level with the development of triptans and at the level of the general understanding of the basic mechanisms, there is still much to learn about these disorders [1].Nociceptive fibers on intracranial vessels such as the superior sagittal sinus (SSS) and the middle meningeal and middle cerebral arteries [2] are central in the understanding of the pathogenesis of neurovascular headache. These vessels are innervated by myelinated Aδ-and unmyelinated C-fibers from the trigeminal ganglion [3]. The system consists of bipolar neurons with cell bodies that reside in the trigeminal ganglion and project to the dura mater and the SSS as well as the major cerebral arteries at the base of the brain, while the central projection is to the trigeminal nucleus caudalis (TNC) in the caudal medulla oblongata and in the cervical spinal cord at the C1 and C2 levels [4]. J Headache Pain (2003) 4:156-163 DOI 10.1007 Immunoreactivity of NOS, CGRP, PACAP, SP and VIP in the trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2 of the cat Abstract The aim of the present study was to map the presence of neurotransmitters and nitric oxid synthase (NOS) in the trigeminal nucleus caudalis and cervical spinal cord of cat. Immunocytochemistry was used to map the presence of neuronal NOS, calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating peptide (PACAP), substance P (SP) and vasoactive intestinal peptide (VIP). The superior sagittal sinus (SSS) was stimulated electrically for 2h (0.3 Hz, 0.25 ms duration, 120 V) to examine if this would lead to depletion of the neurotransmitters. Numerous SP-and CGRP-positive nerve fibers (but no cells) were found in the trigeminal nucleus caudalis (TNC) and in Rexed lamina I and II°of the dorsal horn at C1/C2 level of the spinal cord. Moderate amounts of PACAP-and NOS-positive nerve fibers were also seen in these areas while there were only few VIP-positive fibers. There was no observable difference in the amount of immunoreactivity of NOS or the neuropeptides between stimulated and control cats. The stimulation resulted in marked c-fos immunoreactivity in the same regions of the TNC. The bipolar trigeminal neurons project to the TNC and C1/C2 areas with fibers containing neuropeptides and NOS. Stimulation of the SSS for 2 h was not sufficient to cause noticeable depletion.

Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level

“…CGRP positive fibers were found in laminae I and II. Similar staining pattern has been demonstrated previously in the chick, quail dorsal horn of the spinal cord [31] and in the cat [32]. In addition, we observed some CGRP positive neurons and fibers close to the central canal (laminae X).…”

Neurobiology in primary headaches

“…A marked increase of the immediate early gene c-fos in laminae I and II of the TNC and in the superficial layers of the C1 and C2 regions can be seen upon stimulation of the middle meningeal artery, the superior sagittal sinus or the trigeminal ganglion in monkeys and cats [80,101,115]. However, the expression of neuropeptides in the brainstem is unaltered during 2 hours of superior sagittal sinus stimulation [27]. The c-fos response is reduced by anti-migraine drugs, such as triptans [116,118].…”

“…there is a moderate supply of CGRP and PACAP fibres in these areas while NOS or VIP fibres were not seen [27].…”

No Change in Interictal PACAP Levels in Peripheral Blood in Women With Chronic Migraine

“…Tracing studies have revealed that VIP‐positive nerves originate in the sphenopalatine and otic ganglia, while PACAP‐positive neurons are found both in the above parasympathetic ganglia, but also in the human trigeminal ganglion, where there is no VIP immunoreactivity . The localization of PACAP to both parasympathetic and sensory systems would suggest that, unlike VIP, the role of this peptide is dual on vasomotor function and sensory mechanisms . This could explain that PACAP infusion into migraineurs triggers migraine and indeed produces vasodilatation and, occasionally, headache in nonmigraine subjects, while VIP, a more potent cranial vasodilator, does not induce such headache …”

“…36 The localization of PACAP to both parasympathetic and sensory systems would suggest that, unlike VIP, the role of this peptide is dual on vasomotor function and sensory mechanisms. [37][38][39] This could explain that PACAP infusion into migraineurs triggers migraine 21 and indeed produces vasodilatation 40 and, occasionally, headache in nonmigraine subjects, while VIP, a more potent cranial vasodilator, does not induce such headache. 41 This study has some limitations.…”