Bedeutung von Calcitonin gene-related peptide (CGRP) in der Entstehung der zentralen trigeminalen Sensibilisierung in einem tierexperimentellen Migränemodell
Zusammenfassung der Projektergebnisse
The aim of the projects was to study the functional relevance and potential therapeutic use of several receptor systems and ion channels relevant for the pathophysiology of migraine using several in vivo models of trigeminal activation and cortical excitability. The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonspecific cation channel located on nociceptive neurons of the peripheral and central nervous systems. Its activation induces the release of calcitonin gene‐related peptide (CGRP). To analyze its functional relevance in migraine we used the non‐pungent TRPV1 receptor agonist olvanil, known to induce neuronal desensitization, to analyze its effect on neurogenic vasodilation of the middle meningeal artery (MMA) and on neuronal activity in the trigeminocervical complex (TCC). The results show that intravenously administered olvanil attenuates neuronal activity in first‐ and second‐order nociceptive neurons and that this effect is the result of a synergistic effect of TRPV1‐mediated desensitization and CB1‐mediated neuronal inhibition suggesting that the combined action on vanilloid and cannabinoid systems may offer a promising approach for the acute treatment of migraine. Experimental studies suggest that the NMDA channel plays an important role in migraine but clinical studies investigating its use as a pharmacological target have not reflected these results. To analyze this discrepancy further, the NMDA open channel blockers magnesium and memantine were administered intravenously and their effect on nociceptive neuronal activity in the TCC was measured with electrophysiological recording techniques. In contrast to previous studies in which substances were microiontophoresed into specific anatomical regions of the CNS, we did not observe an attenuating effect when magnesium and memantine were administered intravenously suggesting that the drug concentration at the site of action, that is achievable through a systemic administration, does not suffice to exert an inhibitory effect on nociceptive trigeminal activity. From a functional perspective the hypothalamus plays a prominent role in the early phases of a migraine attack as it is involved in the induction of premonitory symptoms and it links migraine to the circadian rhythm. To elucidate the functional relevance of the hypothalamic orexinergic system in migraine and to analyze its use as a pharmacological target, we analyzed the influence of a dual orexin receptor antagonist (DORA‐12) on neurogenic vasodilation, neuronal activity in the TCC and susceptibility for induction of cortical spreading depression (CSD). The results show, that DORA‐12 is able to inhibit neuronal activity on first‐ and second‐order neurons as well as to elevate the threshold for the experimental induction of CSD. The results therefore show in several in vivo models of migraine, that the orexinergic system may modulate the trigeminal system and further suggest a potential efficacy for the treatment of migraine and migraine aura. From a genetic perspective, the T44A missense mutation in the casein kinase 1δ gene appears to link migraine to the circadian rhythm, especially to the familial advanced sleep phase syndrome (FASPS). To elucidate the functional consequence of this mutation in the context of migraine, transgenic mice carrying the T44A mutation were stimulated on the superior sagittal sinus (SSS) and neuronal activity was measured indirectly through immunohistochemical Fos staining. The results show that the T44A mutation leads to a higher level of neuronal activity in the TCC that does not further increase upon electrical stimulation of the SSS, suggesting the existence of a supra‐medullary focus in migraine with aura.
Projektbezogene Publikationen (Auswahl)
- Intracisternal injection of Inflammatory Soup activates the trigeminal nerve system. Cephalalgia, November 2009; 29 (11): 1212‐7
J. Hoffmann, L. Neeb, H. Israel, F. Dannenberg, F. Triebe, U. Dirnagl, U. Reuter
- Reversible cerebral vasoconstriction associated with orgasmic headache. J Neurol Neurosurg Psychiatry, September 2009; 80 (9): 959
J. Hoffmann, L. Harms, Klingebiel R
- Hypoxic brain injury sparing the posterior circulation. Neurology, May 2010; 74 (18): 1476
J. Hoffmann, K. Erb, R. Klingebiel, E. Siebert
- Is the TRPV1 receptor relevant to migraine? Journal Watch Neurology 2011; 13 (5): 38‐39
J. Hoffmann
- Recent advances in headache research. Expert Rev Neurother 2011; 11 (10): 1379‐81
J. Hoffmann
- Weather sensitivity in migraineurs. J Neurol 2011; 258 (4): 596‐602
J. Hoffmann, H. Lo, L. Neeb, U. Reuter
- New Agents for Acute Treatment of Migraine: CGRP Receptor Antagonists and INOS Inhibitors. Curr Treat Options Neurol 2012; 14 (1): 50‐9
J. Hoffmann, P.J. Goadsby
- Olvanil acts on transient receptor potential vanilloid channel 1 and cannabinoid receptors to modulate neuronal transmission in the trigeminovascular system. Pain 2012; 153 (11): 2226‐32
J. Hoffmann, W. Supronsinchai, A.P. Andreou, O. Summ, S. Akerman, P.J. Goadsby
- Primary trigeminal afferents are the main source for stimulus‐induced CGRP release into jugular vein blood and CSF. Cephalalgia 2012; 32 (9): 659‐67
J. Hoffmann, S. Wecker, L. Neeb, U. Dirnagl, U. Reuter
(Siehe online unter https://doi.org/10.1177/0333102412447701) - Evidence for Orexinergic Mechanisms in Migraine. Neurobiology of Disease, Volume 74, February 2015, Pages 137-143
J. Hoffmann, W. Supronsinchai, S. Akerman, A.P. Andreou, C.J. Winrow, J. Renger, R. Hargreaves, P.J. Goadsby
(Siehe online unter https://doi.org/10.1016/j.nbd.2014.10.022)
