Functional immunohistochemistry of neuropeptides and nitric oxide synthase in the nerve fibers of the supratentorial dura mater in an experimental migraine model

Abstract

The supratentorial cerebral dura of the albino rat is equipped with a rich sensory innervation both in the connective tissue and around blood vessels, which includes nociceptive axons and their terminals; these display intense calcitonin gene-related peptide (CGRP) immunoreactivity. Stereotactic electrical stimulation of the trigeminal (Gasserian) ganglion, regarded as an experimental migraine model, caused marked increase and disintegration of club-like perivascular CGRP-immunopositive nerve endings in the dura mater and induced an apparent increase in the lengths of CGRP-immunoreactive axons. Intravenous administration of sumatriptan or eletriptan, prior to electrical stimulation, prevented disintegration of perivascular terminals and induced accumulation of CGRP in terminal and preterminal portions of peripheral sensory axons. Consequently, immunopositive terminals and varicosities increased in size; accumulation of axoplasmic organelles resulted in the "hollow" appearence of numerous varicosities. Since triptans exert their anti-migraine effect by virtue of agonist action on 5-HT(1D/B) receptors, we suggest that these drugs prevent the release of CGRP from perivascular nerve terminals in the dura mater by an action at 5-HT(1D/B) receptors. Nitroglycerine (NitroPOHL), given subcutaneously to rats, induces increased beading of nitric oxide synthase (NOS)-immunoreactive nerve fibers in the supratentorial cerebral dura mater, and an apparent increase in the number of NOS-immunoreactive nerve fibers in the dural areas supplied by the anterior and middle meningeal arteries, and the sinus sagittalis superior. Structural alterations of nitroxidergic axons innervating blood vessels of the dura mater support the idea that nitric oxide (NO) is involved in the induction of headache, a well-known side effect of coronary dilator agents.

Sumatriptan Causes Parallel Decrease in Plasma Calcitonin Gene-Related Peptide (CGRP) Concentration and Migraine Headache During Nitroglycerin Induced Migraine Attack

“…It has been shown that 5-HT 1B and 5-HT 1D receptors are expressed in the human trigeminal ganglion and they are colocalized with CGRP and nitric oxide synthase (10). Activation of these receptors decreases CGRP release from the trigeminal perivascular axons (4,5,7,8,(27)(28)(29)(30)(31). On Table 1 Headache scores and plasma CGRP concentrations, in two patient groups, before and 60 min after the administration of sumatriptan.…”

CGRP and NO in the Trigeminal System: Mechanisms and Role in Headache Generation

“…CGRP Release Upon Noxious Stimulation.— Following stereotactic electrical stimulation of the rat trigeminal ganglion, the normal “beads‐on‐a‐string” appearance of CGRP‐immunoreactive nerve fibers in the dura changed, and thickened varicosities were found 65 . The same treatment caused depletion of CGRP immunoreactivity in the caudal spinal trigeminal nucleus 66 .…”

Investigation of the immunoreactivities of NOS enzymes and the effect of sumatriptan in adolescent rats using an experimental model of migraine

“…It has been reported that sumatriptan inhibits the NO response by inhibiting trigeminal activation and CGRP release [33]. Similarly, it has been suggested that triptans prevent the release of CGRP from perivascular nerve terminals in the dura mater by an action at 5-HT 1B/1D receptors [34]. Suwattanasophon et al have shown that sumatriptan pretreatment attenuated the nitroglycerin-evoked expression of nNOS in trigeminal ganglia, trigeminal nucleus caudalis and perivascular nerve fiber surrounding superior sagittal sinus of the rats.…”