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

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-HTlD agonists, sumatriptan and N-methyl-3-(1-methyl-1-piperidinyl)-1H-indole-5-ethane sulphonamide (GR 85548).2 Ketanserin (1 gM) and methiothepin (1 gM) 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 MM (n=3) (geometric means and 95% confidence limits). 4 Ketanserin (0.1 or 1 UM) 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 gM) (n = 4). 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-HTLIT1 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.

Endogenously released 5-HT inhibits A and C fiber-evoked synaptic transmission in the rat spinal cord by the facilitation of GABA/glycine and 5-HT release via 5-HT2A and 5-HT3 receptors

“…Ketanserin failed to overturn MSR inhibition by bath-applied 5-HT in several previous studies (Crick and Wallis, 1991;Elliott and Wallis, 1992;Manuel et al, 1995), but in our study, MRS inhibition in response to bath-applied 5-HT was also reversed by ketanserin. 5-HT1D-like receptors rather than 5-HT2A receptors have been proposed to mediate ketanserin-sensitive MSR inhibition (Manuel et al, 1995). Interestingly, pCA provoked a particularly long blockade of MSR in the presence of GR 127935 (a 5-HT1B/D receptor antagonist), which was reversed by ketanserin.…”

“…However, ketanserin failed to reverse MSR blockade by bath-applied 5-HT in previous reports (Crick and Wallis, 1991;Elliott and Wallis, 1992;Manuel et al, 1995).…”

“…Interestingly, pCA provoked a particularly long blockade of MSR in the presence of GR 127935 (a 5-HT1B/D receptor antagonist), which was reversed by ketanserin. This suggests that GR 127935 has an agonistic effect on 5-HT1D receptors (Manuel et al, 1995;Pauwels et al, 1996). Therefore, in this study, we have not examined the effect of GR 127935 at higher concentrations.…”

SB‐224289–a novel selective (human) 5‐HT1B receptor antagonist with negative intrinsic activity

“…However at the h5-HT 1D cloned receptors used in this study, where it has been reported that there is no or little receptor reserve , the same pattern of intrinsic activity is seen suggesting that the partial agonism produced by GR127935 may be re¯ected at native 5-HT 1D receptors. Partial agonism has been reported for GR127935 in the rat neonatal spinal cord thought to contain 5-HT 1D -like receptors (Manuel et al, 1995). To reiterate, the great advantage of SB-224289 over the existing 5-HT 1B receptor antagonists GR127935 and SB-216641 is that this compound exhibits no positive intrinsic activity even in recombinant systems with high receptor reserve.…”

Pharmacological characterization of serotonin receptor subtypes modulating primary afferent input to deep dorsal horn neurons in the neonatal rat

“…Interestingly, Huang & Peroutka (1987) reported that at least 33% of the total 5-HT binding sites in the rat spinal cord are distinct from 5-HT 1A , 5-HT 1B or 5-HT 2C . Since like 5-HT 1A&B receptors, the 5-HT 1D , 5-HT 1E , and 5- HT 1F receptors are negatively coupled to adenylate cyclase (Barnes & Sharp, 1999), they are also likely to produce synaptic depression (see Manuel et al, 1995). Though not presently investigated, these receptors may also contribute to the widespread depressant action of 5-HT.…”