Ketanserin‐sensitive depressant actions of 5‐HT receptor agonists in the neonatal rat spinal cord

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Abstract
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-mettiyl-1-piperidinyl)-lH-indole-5-ethane sulphonamide (GR 85548). 2 . Ketanserin (1 μm) and methiothepin (1 μm) 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, 2.1–6.2nM (n = 4), by sumatriptan was 15.2, 12.9–18.0nM (n= 32), by GR 85548 was 18.4, 11.7–29.1 nm (n= 12), by methysergide was 29.8,10.2–87.1nM(n=4) and by 8-OH-DPAT was 0.21,0.11-0.43 μm (n = 3) (geometric means and 95% confidence limits). 4 . Ketanserin (0.1 or 1 μm) 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 μm) (n = 4). 5 . Methiothepin (1 μm) antagonized competitively responses to GR 85548 (apparent pA2 7.7, unpaired data, n = 5). 6 . Mianserin (0.3μm), 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 μm), (+)-propranolol (0.5 or 1 μm) or spiroxatrine (0.1 μm), and depression of MSR by 8-OH-DPAT was not blocked by spiroxatrine (0.1 μm). (±)-Cyanopindolol (0.1 and 1 μm) 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-oxa-diazol-3-yl) [1, 1-biphenyl]-4-carboxamide (GR 127935, 30 nm to 1μm) 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 1-3nM 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-HT1Dα 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.