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 mu M) and methiothepin (1 mu M) 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 mM (n=4) and by 8-OH-DPAT was 0.21, 0.11-0.43 mu M (n=3) (geometric means and 95% confidence limits). 4 Ketanserin (0.1 or 1 mu M) antagonized competitively responses to sumatriptan (apparent pA(2) 7.8 +/- 0.1, n=5), GR 85548 (apparent pA(2) 7.6, unpaired data, n=5), methysergide (apparent pA(2) 7.9 +/- 0.12, n=4) and 8-OH-DPAT (apparent pA(2) 8.3 +/- 0.1, n=3). Concentration-response curves to 5-CT showed a smaller, parallel shift to the right (apparent pA(2) 6.8 +/- 0.1, n=4), but responses to 5-HT were unaffected by ketanserin (1 mu M) (n=4). 5 Methiothepin (1 mu M) antagonized competitively responses to GR 85548 (apparent pA(2) 7.7, unpaired data, n=5). 6 Mianserin (0.3 mu M), 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 mu M), (+/-)-propranolol (0.5 or 1 mu M) or spiroxatrine (0.1 mu M), and depression of MSR by 8-OH-DPAT was not blocked by spiroxatrine (0.1 mu M). (+/-)-Cyanopindolol (0.1 and 1 mu M) itself induced a slow depression of the MSR. 8 The novel 5-HTID 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 mu M) 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.