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- Title
Agonist actions of dihydroergotamine at 5-HT[sub2B] and 5-HT[sub2C] receptors and their possible relevance to antimigraine efficacy.
- Authors
Schaerlinger, B.; Hickel, P.; Etienne, N.; Guesnier, L.; Maroteaux, L.
- Abstract
1 The pharmaceutical compound, dihydroergotamine (DHE) is dispensed to prevent and reduce the occurrence of migraine attacks. Although slill controversial, the prophylactic effect of this drug is believed to be caused through blockade and or activation of numerous receptors including serotonin (5-HT) receptors of the 5-HT[sub2] subtype. 2 To elucidate if 5-HT[sub2] receptors (5-HT[sub2]Rs) may he involved in DHE prophylactic effect, we performed investigations aimed to determine the respective pharniacological profile of DHE and of its major metabolite 8'-hydroxy-DHF. (8'-OH-DHE)cgmp at the 5-HT[sub2B] and 5-HT[sub2C] Rs by binding, inositol triphosphate (IP[sub3]) or cyclic GMP (cGMP) coupling studies in transfected fibroblasts. 3 DHE and 8'-OH-DHE are competitive compounds at 5-HT[sub2B] and 5-HT[sub2C] Rs, 8'-OH-DHE interaction af (5-HT[sub2B]Rs) was best fitted by a biphasic competition curve and displayed the highest affinity with a K[sub1] of 5 nm These two compounds acted as agonists for both receptors in respect to cGMP production with pEC[sub50] of 8.32±0.09 for 8'-OH-DHE at 5-HT[sub2B] and 7.83±0.06 at 5-HT[sub2C] Rs. 4 Knowing that the antimigraine prophylactic effect of DUE is only observed after long-term treatment, we chronically exposed the recomhinanl cells to DHE and 8'-OH-DHE. The number of 5-HT[sub2B]R-binding sites was always more affected than 5-HT[sub2C] Rs. At 5-HT[sub2B]Rs. 8'-OH-DIIE was more effective than DHE. with an uncoupling that persisted for more than 40h for IP[sub3] or cGMP. By contrast, the 5-HT[sub2C]R coupling was reversible after either treatment. 5 Chronic exposure to 8'-OH-DHE caused a persistent agonist-mediated desensitisation of 5-HT[sub2B], but not 5-HT[sub2C]Rs. This may be of relevance to therapeutic actions of the compound.
- Subjects
HEADACHE treatment; MIGRAINE; SEROTONIN; CYCLIC guanylic acid; INOSITOL phosphates; RECEPTOR antibodies
- Publication
British Journal of Pharmacology, 2003, Vol 140, Issue 2, p277
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0705437