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‐HT 1D agonists, sumatriptan and N‐methyl‐3‐(1‐mettiyl‐1‐piperidinyl)‐lH‐indole‐5‐ethane sulphonamide (GR 85548). 2 . Ketanserin (1 μm) and methiothepin (1 μ 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 IC 50 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 n m ( 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 μ m ( n = 3) (geometric means and 95% confidence limits). 4 . Ketanserin (0.1 or 1 μm) 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 μm) ( n = 4). 5 . Methiothepin (1 μ m ) antagonized competitively responses to GR 85548 (apparent pA 2 7.7, unpaired data, n = 5). 6 . Mianserin (0.3μm), a concentration sufficient to cause substantial block of 5‐HT 2C ‐mediated responses but have only a small effect on 5‐HT 1D ‐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 μ m ), (+)‐propranolol (0.5 or 1 μm) or spiroxatrine (0.1 μ m ), 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‐HT 1d 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 n m 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‐HT 1Dα 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.