Les recepteurs de la serotonine dans les traitements de la migraine : aspects neuronaux et vasculaires chez l'humain

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.

The potent 5-HT3 receptor antagonist (R)-zacopride labels an additional high affinity site in the central nervous system

The binding characteristics of [3H](S)-zacopride were investigated in membranes from the rat entorhinal cortex and NG 108-15 clonal cells. In contrast to [3H](S)-zacopride which bound solely to 5-HT3 receptors, [3H](R)-zacopride recognized another class of binding sites, called the (R)-sites, in both membrane preparations. In addition to (R)-zacopride (Ki=3–11 nM), only (R)-iodo-zacopride, (R)-dechloro-zacopride, prazosin and mianserin exhibited high to moderate affinity for the (R)-sites, whose possible functions remain to be established