Ketanserin-sensitive depressant actions of 5-HT receptor agonists in the neonatal rat spinal cord.
1. The monosynaptic reflex (MSR), recorded in vitro from the neonatal rat spinal cord, was depressed by 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), methysergide and R(+)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and also by the selective 5-HT1D agonists, sumatriptan and N-methyl-3-(1-methyl-1-piperidinyl)-1H-indole-5-ethane sulphonamide (GR 85548). 2. Ketanserin (1 microM) and methiothepin (1 microM) reduced the duration of depressions elicited by 5-CT, but not those produced by 5-HT, sumatriptan, GR 85548, methysergide or 8-OH-DPAT. 3. The IC50 for MSR depression by 5-CT was 3.6, 2.1-6.2 nM (n = 4), by sumatriptan was 15.2, 12.9-18.0 nM (n = 32), by GR 85548 was 18.4, 11.7-29.1 nM (n = 12), by methysergide was 29.8, 10.2-87.1 nM (n = 4) and by 8-OH-DPAT was 0.21, 0.11-0.43 microM (n = 3) (geometric means and 95% confidence limits). 4. Ketanserin (0.1 or 1 microM) antagonized competitively responses to sumatriptan (apparent pA2 7.8 +/- 0.1, n = 5), GR 85548 (apparent pA2 7.6, unpaired data, n = 5), methysergide (apparent pA2 7.9 +/- 0.12, n = 4) and 8-OH-DPAT (apparent pA2 8.3 +/- 0.1, n = 3). Concentration-response curves to 5-CT showed a smaller, parallel shift to the right (apparent pA2 6.8 +/- 0.1, n = 4), but responses to 5-HT were unaffected by ketanserin (1 microM) (n = 4). 5. Methiothepin (1 microM) antagonized competitively responses to GR 85548 (apparent pA2 7.7, unpaired data, n = 5). 6. Mianserin (0.3 microM), a concentration sufficient to cause substantial block of 5-HT2C-mediated responses but have only a small effect on 5-HT1D-mediated actions, caused a small, non-parallel shift of the concentration-response curve to sumatriptan. 7. Depression of the MSR by sumatriptan was not blocked by (+/-)-cyanopindolol (0.1 microM), (+/-)-propranolol (0.5 or 1 microM) or spiroxatrine (0.1 microM), and depression of MSR by 8-OH-DPAT was not blocked by spiroxatrine (0.1 microM). (+/-)-Cyanopindolol (0.1 and 1 microM) itself induced a slow depression of the MSR. 8. The novel 5-HT1D antagonist, N-[4-methyl-1-piperazinyl) phenyl]2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide (GR 127935, 30 nM to 1 microM) caused a concentration-related depression of the reflex (up to 50%) usually slow in onset. Neither with these concentrations nor with concentrations in the range 1-3 nM was there any unequivocal blockade of responses to sumatriptan. 9. It is concluded that sumatriptan, GR 85548, methysergide and 8-OH-DPAT depress the MSR in the neonate rat spinal cord via ketanserin-sensitive receptors, which have some similarities to 5-HT1D alpha receptors but which are not blocked by GR 127935. 5-HT released by tryptaminergic pathways may act via the same receptors to depress the MSR. 5-HT applied to the cord probably acts via a different, possibly novel 5-HT receptor to depress the MSR.
Manuel
N A
NA
Unit of Physiology, School of Molecular and Medical Biosciences, University of Wales College of Cardiff.
Wallis
D I
DI
Crick
H
H
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D003864:Depression, Chemical; D004146:Dioxanes / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D007650:Ketanserin / Q000494:pharmacology*; D008297:Male; D009046:Motor Neurons / Q000187:drug effects; D010069:Oxadiazoles / Q000494:pharmacology; D010869:Pindolol / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology; D012023:Reflex, Monosynaptic / Q000187:drug effects; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D013141:Spiro Compounds / Q000494:pharmacology; D018170:Sumatriptan / Q000037:antagonists & inhibitors / Q000494:pharmacology
D004146:Dioxanes; D018492:Dopamine Antagonists; D010069:Oxadiazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013141:Spiro Compounds; C090701:GR 127935; D012701:Serotonin; C047975:cyanopindolol; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D018170:Sumatriptan; C047087:5-carboxamidotryptamine; D007650:Ketanserin; D011433:Propranolol; D010869:Pindolol; C018387:spiroxatrine