Two classes of antimigraine drugs specifically target serotonin (5-HT) receptors: agonists of the 5-HT1B/1D receptors and antagonists of the 5-HT2B/2C receptors. They are respectively used in symptomatic and prophylactic treatments. The study of their mechanisms of action can assist in better uncovering the mechanisms underlying migraine. / Using molecular, pharmacological, immunocytochemical and histochemical approaches, we have studied the distribution and the role of the 5-HT receptors targeted by these medications in human trigeminal ganglion (TG) and extracerebral vessels (PV), two tissues of primary importance in migraine pathology. / We first focused our study of symptomatic treatment on sumatriptan, a drug which works with high efficacy but can trigger cardiac adverse-effects. Two mechanisms have been suggested to explain its therapeutic effect during migraine headache: the contraction of overly dilated PV and the inhibition of a neurogenic inflammation within meningeal tissues following the stimulation of TG. Sumatriptan's cardiac effects have been associated with the contraction of coronary artery (CA) in high-risk patients. / In order to help develop drugs which minimize such harmful side-effects, we have identified in human the type and distribution of sumatriptan-sensitive receptors in TG, PV and CA. As sumatriptan has a high affinity for the 5-HT1B, 5-HT1D and 5-HT1F receptor subclasses, we used reverse transcriptase-polymerase chain reaction (RTPCR) to distinguish between them. We have demonstrated the non-selective distribution of the RNA for the 5-HT1D and 5-HT1F receptors in human TG and some PV whereas the 5-HT1B receptor mRNA was mainly expressed in PV. 5-HT1B and 5-HT1F receptor RNA have also been detected in the CA. / We then used an in vitro vascular reactivity assay with receptor-selective agonists and showed that of these three receptor subclasses, only the 5-HT1B receptor elicits vasoconstriction in PV. Agonists for 5-HT1D and 5-HT1F could therefore potentially be anti-migraine compounds devoid of vascular adverse-effects. / We followed this study by examining the medications used in prophylaxis which are antagonists at either 5-HT2B or 5-HT2C receptors. It has been suggested that stimulation of such receptors in the endothelium of cerebral vessels could trigger migraine via the release of nitric oxide, a compound both nociceptive and vasodilator. We have successfully demonstrated using RT-PCR that the 5-HT2B but not the 5-HT2C receptor RNA is present in cerebral vessels. We further utilized RT-PCR and immunocytochemistry to precisely localize the receptor and show its presence not, only in the endothelium but also the smooth muscle of cerebral vessels. (Abstract shortened by UMI.)
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.36756 |
| Date | January 2000 |
| Creators | Bouchelet, Isabelle. |
| Contributors | Hamel, E. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | French |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Neuroscience.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001771757, proquestno: NQ69856, Theses scanned by UMI/ProQuest. |
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