Difference between revisions of "Encrypted code: Hyperexcitability of the trigeminal system"

The concentration of extracellular glutamate in 13 patients affected by cavernous angioma<ref>von Essen C, Rydenhag B, Nystrom B, Mozzi R, van Gelder N, Hamberger A. High levels of glycine and serine as a cause of the seizure symptoms of cavernous angiomas? J Neurochem. 1996;67(1):260–264. [PubMed] [Google Scholar]</ref> was reported to be increased in comparison with physiological concentrations. High levels of glutamate can cause negative effects on the brain through excitotoxic mechanisms, including degeneration of the superficial layer of the retina in a mouse after repeated administration of glutamate, termed “glutamate excitotoxicity”,<ref>Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch. 2010;460(2):525–542. doi: 10.1007/s00424-010-0809-1. [PubMed] [CrossRef] [Google Scholar]</ref> resulting from NMDA receptor hyperactivation .<ref>Meldrum B, Garthwaite J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci. 1990;11(9):379–387. doi: 10.1016/0165-6147(90)90184-A. [PubMed] [CrossRef] [Google Scholar]</ref> In a study in which the trigeminal ganglion neurons were exposed to KCl, the calculated release of glutamate was 10 times greater than the basal level.<ref>Xiao Y, Richter JA, Hurley JH. Release of glutamate and CGRP from trigeminal ganglion neurons: role of calcium channels and 5-HT1 receptor signaling. Mol Pain. 2008;4:12. doi: 10.1186/1744-8069-4-12. [PMC free article] [PubMed] [CrossRef] [Google Scholar]</ref> Further, a significant reduction in the release of potassium-induced glutamate was observed with addition of ω-agatoxin TK, a powerful P/Q calcium channel blocker, while the N-type calcium channel blocker ω-Cgtx conotoxin had a similar effect .<ref>McCleskey EW, Fox AP, Feldman DH, Cruz LJ, Olivera BM, Tsien RW, Yoshikami D. Omega-conotoxin: direct and persistent blockade of specific types of calcium channels in neurons but not muscle. Proc Natl Acad Sci U S A. 1987;84(12):4327–4331. doi: 10.1073/pnas.84.12.4327. [PMC free article] [PubMed] [CrossRef] [Google Scholar]</ref> Nimodipine, an L-type calcium channel blocker, was also found to reduce the amount of potassium-induced glutamate release.<ref>Hockerman GH, Johnson BD, Abbott MR, Scheuer T, Catterall WA. Molecular determinants of high affinity phenylalkylamine block of L-type calcium channels in transmembrane segment IIIS6 and the pore region of the alpha1 subunit. J Biol Chem. 1997;272(30):18759–18765. doi: 10.1074/jbc.272.30.18759. [PubMed] [CrossRef] [Google Scholar]</ref> These studies suggest that the P/Q-, N-, and L-type calcium channels each mediate a significant fraction of depolarization-associated glutamate release.

Glutamate release is obviously a much broader and more complex phenomenon. NMDA, kainate, and AMPA ionotrophic receptors, and the metabotropic glutamate receptors, have been found in the superficial lamina of the trigeminal nucleus caudalis in mice.<ref>Tallaksen-Greene SJ, Young AB, Penney JB, Beitz AJ. Excitatory amino acid binding sites in the trigeminal principal sensory and spinal trigeminal nuclei of the rat. Neurosci Let. 1992;141(1):79–83. doi: 10.1016/0304-3940(92)90339-9. [PubMed] [CrossRef] [Google Scholar]</ref> NMDA and AMPA receptor antagonists can block the transmission of the nociceptive trigeminal-vascular signals <ref>Storer RJ, Goadsby PJ. Trigeminovascular nociceptive transmission involves N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors. Neuroscience. 1999;90(4):1371–1376. doi: 10.1016/S0306-4522(98)00536-3. [PubMed] [CrossRef] [Google Scholar]</ref><ref>Goadsby PJ, Classey JD. Glutamatergic transmission in the trigeminal nucleus assessed with local blood flow. Brain Res. 2000;875(1–2):119–124. [PubMed] [Google Scholar]</ref> and reduce the high level of c-fos observed in the trigeminal nucleus caudalis following cisternal injection of capsaicin.<ref>Waeber C, Moskowitz MA, Cutrer FM, Sanchez Del Rio M, Mitsikostas DD. The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis. Pain. 1998;76(1–2):239–248. [PubMed] [Google Scholar]</ref> Furthermore, micro-injections of ω-agatoxin into the ventrolateral area of the periaqueductal gray cause a facilitatory response of nociceptive activity in the trigeminal nucleus caudalis (TNC) activated by tonic electrical stimulation of the supratentorial parietal dura, adjacent to the middle meningeal artery.<ref>Knight YE, Bartsch T, Kaube H, Goadsby PJ. P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci. 2002;22(5):RC213. [PMC free article] [PubMed] [Google Scholar]</ref> This response can occur through antinociceptive and/or pronociceptive effects, because the presence of P/Q-type calcium channels is required at the synaptic level for the presynaptic action potentials to couple with the neurotransmitter release processes.<ref>Dunlap K, Luebke JI, Turner TJ. Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci. 1995;18(2):89–98. doi: 10.1016/0166-2236(95)93882-X. [PubMed] [CrossRef] [Google Scholar]</ref> Of note, the pre-synaptic afferents in the PAG are positioned on GABAergic inhibitory interneurons and on descending projection neurons. Therefore, the facilitatory effect may be explained by an increased release of GABA, which would indirectly disinhibit the dorsal horn neurons, or by a direct pronociceptive mechanism.<ref>Pan ZZ, Williams JT, Osborne PB. Opioid actions on single nucleus raphe magnus neurons from rat and guinea-pig in vitro. J Physiol. 1990;427:519–532. [PMC free article] [PubMed] [Google Scholar]</ref> These experimental results provide further understanding of the clinical manifestations of pain and central nervous system hyperexcitability found in cases of cerebral cavernous malformations.