Magnitude of 5-HT1B and 5-HT1A receptor activation in guinea-pig and rat brain: evidence from sumatriptan dimer-mediated [35S]GTPgammaS binding responses

The present study reports on G-protein activation by recombinant 5-HT receptors and by native 5-HT1A and 5-HT1B receptors in guinea-pig and rat brain using agonist-stimulated [35S]GTPgammaS binding responses mediated by a new 5-HT ligand, a dimer of sumatriptan. Dimerization of sumatriptan increased the binding affinity for h 5-HT1B (pKi: 9.22 vs. 7.79 for sumatriptan), h 5-HT1D (9.07 vs. 8.08) and also h 5-HT1A receptors (7.80 vs. 6.40), while the binding affinity for h 5-ht1E (6.67 vs. 6.19) and h 5-ht1F (7.37 vs. 7.78) receptors was not affected. Sumatriptan dimer (10 microM) stimulated [35S]GTPgammaS binding mainly in the superficial gray layer of the superior colliculi, hippocampus and substantia nigra of guinea-pig and rat coronal brain sections. This fits with the labelling by the 5-HT1B/1D receptor antagonist [3H] GR 125743. The observed [35S]GTPgammaS binding responses in the substantia nigra are likely to be mediated by stimulation of the 5-HT1B receptor subtype, since they were antagonized by the 5-HT1B inverse agonist SB 224289 (10 microM), and not by the 5-HT2A/1D antagonist ketanserin (10 microM). Quantitative assessment of the [35S]GTPgammaS binding responses in the substantia nigra of rat showed highly efficacious responses for both sumatriptan dimer and its monomer. In contrast, less efficacious agonist responses (51+/-10% and 35+/-13%, respectively) were measured in the guinea-pig substantia nigra. This may suggest that the G-protein coupling efficacy of 5-HT1B receptors is different between the substantia nigra of both species. In addition, the sumatriptan dimer also activated guinea-pig and rat hippocampal 5-HT1A receptors with high efficacy in contrast to sumatriptan. Therefore, dimerization of sumatriptan can be considered as a new approach to transform a partial 5-HT1A agonist into a more efficacious agonist. In conclusion, the sumatriptan dimer stimulates G-protein activation via 5-HT1B receptors besides 5-HT1A receptors in guinea-pig and rat brain. The magnitude of the 5-HT1B receptor responses is superior for sumatriptan and its dimer in rat compared to guinea-pig substantia nigra.     

Glutamate receptors in the enteric nervous system: ionotropic or metabotropic?

Intracellular recording methods were used to investigate actions of glutamate on morphologically identified neurones in the myenteric and submucous plexuses of guinea-pig small intestine. Glutamate evoked a tetrodotoxin-resistant, slowly activating depolarizing response in most of the submucous neurones (86 of 125, 69%) and a smaller number of myenteric neurones (6 of 60, 10%). The depolarizing responses were restricted to S-type neurones with uniaxonal morphology. The group I metabotropic glutamate receptor (mGluRs) agonists quisqualate, 1S, 3R-ACPD and DHPG mimicked the depolarizing action of glutamate. A group I mGluRs antagonist, S-4-carboxyphenylglycine (S-4CPG), suppressed the glutamate responses with an IC50 of 357 microM at 30 microM glutamate. Group II or III mGluRs agonists did not produce depolarizing responses and group II or III mGluRs antagonists did not alter glutamate-evoked depolarization. The ionotropic glutamate receptor (iGluRs) agonists NMDA, AMPA, or kainate did not evoke depolarizing responses and glutamate-evoked depolarization was unaffected by the iGluRs antagonists D-APV, MK-801, or DNQX. No rapidly activating fast depolarizing responses reminiscent of fast excitatory postsynaptic potentials (EPSPs) were ever observed during application of glutamate or AMPA and stimulus-evoked fast EPSPs were unaffected by DNQX. The results suggest that the excitatory action of glutamate on enteric neurones is mediated by group I metabotropic glutamate receptors and that ionotropic glutamate receptors are not involved. The results also suggest that glutamate-mediated fast EPSPs may not be present in myenteric and submucous neurones in guinea-pig small bowel.     

Signalling mechanism coupled to 5-hydroxytryptamine4 receptor-mediated facilitation of fast synaptic transmission in the guinea-pig ileum myenteric plexus

5-hydroxytryptamine (HT)4 receptor agonists stimulate gastrointestinal motility partly by facilitating acetylcholine release from myenteric neurones. However, the signalling mechanisms that couple 5-HT4 receptor activation to increased transmitter release in the myenteric plexus are unknown. We used conventional intracellular electrophysiological methods to record fast excitatory postsynaptic potentials (fEPSPs) from neurones in the guinea-pig ileum myenteric plexus preparation. The substituted benzamide, renzapride, acted at 5-HT4 receptors to facilitate fEPSPs. This response was mimicked by forskolin, an activator of adenylate cyclase. Facilitation of fEPSPs by renzapride and forskolin was not blocked by treating tissues with pertussis toxin (PTX) (2 h, 2 microg mL-1). Facilitation of fEPSPs caused by renzapride was blocked by the non-selective protein kinase inhibitors, staurosporine (1 micromol L-1) and H-8 (30 micromol L-1) and by the selective protein kinase A (PKA) inhibitor, H-89 (10 micromol L-1). These data indicate that 5-HT4 receptors act via a PTX-resistant mechanism to activate PKA. Protein kinase A activation leads to an increase in transmitter release from myenteric nerve terminals and a facilitation of fast excitatory synaptic transmission.     

Sumatriptan fast-disintegrating/rapid-release tablets in the acute treatment of migraine

Sumatriptan is the first serotonin (5-hydroxytryptamine [5-HT](1B/1D)) receptor agonist specifically designed for the acute treatment of migraine. A new sumatriptan fast disintegrating/rapid release tablet (FDT/RRT) using RT technology has been developed to enhance tablet disintegration and dispersion in the stomach with the intention of speeding absorption and onset of effect, hence mitigating the effects on the gastrointestinal dysmotility that typically accompanies the attack. Sumatriptan FDT/RRT is bioequivalent to conventional tablets, although it provides slightly faster absorption during early post-dose interval. Clinical trials indicate that sumatriptan FDT/RRT is rapidly effective in terms of freedom from pain and return to normal activities, both with early and late treatment. The drug is well tolerated. In an oral formulation, which is the patients' preferred dosing route, sumatriptan FDT/RRT may therefore constitute an advance in the management of acute migraine attacks.     

5-Hydroxytryptamine-Mediated Responses in Myenteric Neurons of the Guinea Pig Gastric Corpus: Effect of ICS 205–930 and Cisapride

The effects of serotonin (5-hydroxytryptamine, or 5-HT) on the neurophysiologic behavior of guinea pig gastric myenteric neurons were investigated in vitro using conventional intracellular recording methods. The predominant effect consisted of a brief, rapidly desensitizing depolarization in 48 of 78 neurons. During the depolarization the membrane resistance decreased and the excitability of the neurons increased, as indicated by action potential discharge during previously subthreshold depolarizing current pulses. The fast response to 5-HT was mimicked by the 5-HT₃ receptor agonist 2-methyl-5-HT. Both cisapride and the selective 5-HT₃ receptor antagonist ICS 205–930 dose-dependently reduced the fast 5-HT and 2-methyl-5-HT response. 5-HT evoked in 3 of 78 neurons a long-lasting depolarization in addition to the initial fast response. This response was accompanied by an increased excitability level of the cell. The long-lasting response was blocked by the 5-HT_1p receptor antagonist N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP) and mimicked by the 5-HT_1p receptor agonist 5-hydroxyindalpine (5-OHIP). In most neurons 5-HT had no effect on the cholinergic fast excitatory postsynaptic potentials (fEPSPs) evoked by electrical stimulation of interganglionic fiber tracts. Occasionally, it reduced the fEPSP amplitude. In another subset of neurons it increased the fEPSP amplitude. As a result, the fEPSP reached threshold for spike discharge. The results indicate that the primary effect of 5-HT on myenteric neurons is mediated through 5-HT₃ receptors whereas only a minor proportion of the neurons exhibited 5-HT_1p-mediated responses. ICS 205–930 and cisapride act as 5-HT₃ receptor antagonists in gastric myenteric neurons.     

Inhibition of inflammation-induced thermal hypersensitivity by sumatriptan through activation of 5-HT(1B/1D) receptors

Migraine is effectively treated by drugs acting via 5-HT(1B/1D) receptors; however, the antinociceptive effects of such agents have not been fully investigated, particularly in models in which sensitization may be present. The aim of these studies was to evaluate the effects of the 5-HT(1B/1D) receptor agonist sumatriptan in specific models of pain states: a mouse model of inflammation-induced thermal hyperalgesia and a rat model of nerve injury-induced thermal hyperalgesia. In female mice, following intraplantar injection of carrageenan 225 min earlier, sumatriptan (300 microg/kg intraperitoneally; i.p.) increased paw withdrawal latency (PWL) from 3.1 +/- 0.4 s in the saline group to 5.6 +/- 0.9 s, measured 240 min postcarrageenan (P < 0.05 ANOVA followed by post hoc Dunnett's test). A similar effect was seen in male mice. Sumatriptan was also effective in male mice when given i.p. and subcutaneously 15 min precarrageenan, with a maximum effect at 30 microg/kg (i.p. latency 7.4 +/- 1.3 s compared to saline group, 2.6 +/- 0.7 s; i.v. latency 5.9 +/- 0.8 s compared to saline group, 2.9 +/- 0.3 s; P < 0.05 ANOVA followed by post hoc Dunnett's test). The number of mice required to give a response that could be reliably attributed to sumatriptan (number needed to treat) was calculated using discriminant analysis and found to be 2.6. The ability of sumatriptan to attenuate the carrageenan-induced reduction in PWL was blocked by the mixed 5-HT(1B/1D) receptor antagonist GR-127935 (3 mg/kg i.p.) but not by the 5-HT(1B) receptor antagonist SB-224289 (10 mg/kg i.p.). Sumatriptan had no effect on thermal hyperalgesia induced by sciatic nerve ligation in the rat at any time point. These data demonstrate that sumatriptan attenuates the hypersensitivity to noxious thermal stimuli induced by intraplantar carrageenan.     

Serotonergic functioning in children with oppositional defiant disorder: a sumatriptan challenge study.

BACKGROUND: Several studies support the notion that disturbances in the central serotonergic function are related to impulsive aggression. There is recent evidence from studies on 5-HT(1B) knock-out mice that this specific receptor is involved in impulsive aggressive behavior. The aim of the present study was to investigate 5-HT(1B/1D) receptor functioning in normal intelligent hospitalized children with oppositional defiant disorder (ODD). METHODS: The growth hormone (GH) response to a challenge with the 5-HT(1B/1D) agonist sumatriptan was examined in 20 children with an ODD, of whom 13 had an attention-deficit/hyperactivity disorder comorbidity, and 15 normal control subjects (NC). Blood samples for growth hormone were collected repeatedly between 8:30 and 12:00 AM. Sumatriptan was administered at 10 AM. The effect of stress due to this procedure was assessed by measuring salivary cortisol. RESULTS: The GH response was significantly stronger in the children with ODD. After sumatriptan injection NC children showed a significant increase in cortisol; no such pattern was present in the ODD group. CONCLUSIONS: The results suggest that the postsynaptic 5-HT(1B/1D) receptor is functionally more sensitive in children with ODD.     

Specific antagonism of enteric neural serotonin receptors by dipeptides of 5-hydroxytryptophan: evidence that serotonin is a mediator of slow synaptic excitation in the myenteric plexus

Research on the role of serotonin (5-hydroxytryptamine, 5-HT) in the function of the enteric nervous system has been impeded by the lack of specific inhibitors of the enteric neural actions of 5-HT. Saturable, reversible, high affinity enteric binding sites for 3H-5-HT have recently been characterized and radioautographically located. Affinity for the 3H-5-HT binding site requires an indole ring substituted with a free hydroxyl group. These 3H-5-HT binding sites have been proposed to be enteric neural 5-HT receptors. This hypothesis was tested in the current study by comparing the ability of compounds to inhibit the binding of 3H-5-HT with their electrophysiologically determined actions on myenteric neurons. 5-Methoxytryptamine did not inhibit the binding of 3H-5-HT to enteric membranes and neither mimicked nor antagonized the effects of 5-HT on the membrane potential of myenteric neurons. Two dipeptides of 5-hydroxytryptophan, N-acetyl- and N-hexanoyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP and N-hex-5-HTP-DP) inhibited the binding of 3H-5-HT (K1 = 0.25 microM for 5-HTP-DP and 1.19 microM for N-hex-5-HTP-DP). 5-HTP-DP applied by pressure microejection or superfusion (10 microM) antagonized the slow postsynaptic depolarization of myenteric neurons evoked by microejection of 5-HT. 5-HTP-DP also blocked the 5-HT-induced presynaptic reduction in amplitude of nicotinic fast synaptic potentials; however, 5-HTP-DP itself did not affect these responses. Moreover, 5-HTP-DP also failed to affect responses of myenteric neurons to microejected substance P, their muscarinic response to acetylcholine, or antidromic action potentials. In contrast, both dipeptides blocked the slow synaptic potentials seen in type II/AH neurons following stimulation of fiber tracts in interganglionic connectives. These data support the hypotheses that enteric 3H-5-HT binding sites are enteric neural 5-HT receptors, that dipeptides of 5-hydroxytryptophan are specific antagonists at these receptors, and that 5-HT is one of the mediators of slow synaptic potentials in the myenteric plexus.     

Evidence for serotonin influencing the thalamic infiltration of mast cells in rat

Serotonin (5-HT) is involved in neuroimmunomodulation. We analyzed the effects of sumatriptan, a 5-HT(1B/1D) receptor agonist, and ondansetron, a 5-HT(3) receptor antagonist, on thalamic mast cell (TMC) population, the only immunocytes known to infiltrate the brain in physiological conditions. Only sumatriptan was effective, significantly increasing TMC numbers versus controls, and especially those containing 5-HT. 5-HT(1B) receptors are concentrated in the median eminence on non-serotonergic axonal endings, probably hypothalamic terminal fibers, involved in hypothalamic-pituitary neuroendocrine modulating processes. TMC variations could reflect serotonergic actions on these fibers. TMCs would thus be cellular interfaces mediating immune action in the nervous system in relation with the hormonal status of the organism.     

Effect of sumatriptan, a selective 5-HT1-like receptor agonist, on pial vessel diameter in anaesthetised cats.

The action of sumatriptan, a selective 5-HT1-like receptor agonist that is effective for the acute treatment of migraine, was compared on pial vessel diameter following perivascular or intravenous administration to anaesthetised cats. Sumatriptan (0.01-10 microM), when microinjected perivascularly, caused a decrease in pial artery diameter (maximum change of -19 +/- 9%; mean +/- SD) but had no effect on the diameter of pial veins. Sumatriptan (1 microM)-induced pial artery vasoconstriction was unaffected by coadministration of ketanserin (1 microM) or ondansetron (1 microM) but was significantly (p less than 0.01) attenuated by methiothepin (1 microM). Intravenous infusion of a clinically effective dose of sumatriptan (64 micrograms/kg/10 min) caused selective carotid vasoconstriction (22 +/- 6% increase in carotid vascular resistance with little or no change in blood pressure or heart rate) and no change in pial artery diameter, although sumatriptan (1 microM) administered perivascularly in these animals before and after the infusion caused pial artery vasoconstriction. These results demonstrate that perivascularly administered sumatriptan causes pial artery vasoconstriction via activation of 5-HT1-like receptors. However, intravenously administered sumatriptan does not cause pial artery vasoconstriction, which suggests that sumatriptan does not readily penetrate the cerebrovascular intima.     

Antimigraine drug sumatriptan increases blood flow velocity in large cerebral arteries during migraine attacks.

Sumatriptan, a novel selective 5-hydroxytryptamine1d (5-HT1d) receptor agonist, which is highly effective in the acute treatment of migraine attacks, blocks dural neurogenic plasma extravasation and constricts cranial blood vessels in animal experiments. We measured intra- and extracranial blood flow velocities (BFV) with a transcranial Doppler device in 67 patients during a spontaneous migraine attack, before and after treatment with 3 mg or 6 mg subcutaneous sumatriptan or placebo. Sumatriptan, but not placebo, significantly increased BFV (cm/sec) in the internal carotid and middle cerebral arteries on both sides, without detectably changing the BFV in the common and external carotid arteries. The rise in BFV increased with the dose of sumatriptan, parallel to an increase in proportion of patients improved. There were no significant changes in heart rate, blood pressure, or respiratory frequency after treatment with sumatriptan. The increase in BFV probably reflects vasoconstriction of the large basal intracranial arteries, which may be a mechanism for the antimigraine action of sumatriptan.     

Neurogastroenterology of tegaserod (HTF 919) in the submucosal division of the guinea-pig and human enteric nervous system.

Actions of the 5-HT(4) serotonergic receptor partial agonist, tegaserod, were investigated on mucosal secretion in the guinea-pig and human small intestine and on electrophysiological behaviour of secretomotor neurons in the guinea-pig small intestinal submucosal plexus. Expression of 5-HT(4) receptor protein and immunohistochemical localization of the 5-HT(4) receptor in the submucosal plexus in relation to expression and localization of choline acetyltransferase and the vesicular acetylcholine (ACh) transporter were determined for the enteric nervous system of human and guinea-pig small intestine. Immunoreactivity for the 5-HT(4) receptor was expressed as ring-like fluorescence surrounding the perimeter of the neuronal cell bodies and co-localized with the vesicular ACh transporter. Exposure of mucosal/submucosal preparations to tegaserod in Ussing chambers evoked increases in mucosal secretion reflected by stimulation of short-circuit current. Stimulation of secretion had a relative high EC(50) of 28.1 +/- 1.3 mumol L(-1), was resistant to neural blockade and appeared to be a direct action on the secretory epithelium. Tegaserod acted at presynaptic 5-HT(4) receptors to facilitate the release of ACh at nicotinic synapses on secretomotor neurons in the submucosal plexus. The 5-HT(2B) receptor subtype was not involved in actions at nicotinic synapses or stimulation of secretion.     

IL-1β and IL-6 excite neurones and suppress cholinergic neurotransmission in the myenteric plexus of the guinea pig

The effects of the inflammatory mediators interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) on myenteric neurones were investigated by intracellular recordings in a conventional myenteric plexus preparation of guinea pig ileum. Micropressure ejection of IL-1beta and IL-6 (10-7 mol L-1) both caused an excitatory effect in, respectively, 19% (13/70) and 7% (5/70) of the myenteric neurones. The IL-1beta-induced depolarizations were inhibited by superfusion of the IL-1beta receptor antagonist. The responses seen were tetrodotoxin-resistant, indicating a direct neuronal effect. Responses to both cytokines were seen in nitric oxide synthase-immunoreactive as well as choline acetyltransferase-immunoreactive neurones. In addition, both IL-1beta and IL-6 reversibly caused a presynaptic inhibition of acetylcholine release from cholinergic nerve terminals. Both cytokines had no effect on the slow excitatory postsynaptic potentials. Therefore, we can conclude that the inflammatory mediators IL-1beta and IL-6 can act as excitatory neuromodulators of gastrointestinal motility through direct excitatory actions on a subset of myenteric neurones and through the presynaptic inhibition of acetylcholine release.     

5-HT response of rat hippocampal pyramidal cell bodies.

Serotonin (5-HT) responses of pyramidal neurones freshly dissociated from rat ventral hippocampal CA1 region were investigated by using nystatin-perforated whole-cell recording. These dissociated neurones lack most of the dendrites and axons. Application of nanomolar concentrations of 5-HT induced outward current with an increase of membrane conductance at a holding potential (VH) of -40 mV. The current was mimicked by alpha-methyl-5-HT (5-HT2 receptor family agonist), but not by 8-OH-DPAT (5-HT1 receptor family agonist). Ketanserin (5-HT2 receptor family antagonist) and spiperone (5-HT1A and 5-HT2 receptor family antagonist) blocked the current in a concentration dependent manner. These results suggests that 5-HT-induced outward current is mediated by the activation of 5-HT2 receptor family in the cell bodies of hippocampal pyramidal neurones.     

Influence of a 5HT1 receptor agonist on gastric accommodation and initial transpyloric flow in healthy subjects

Sumatriptan, a 5HT1 receptor agonist, inhibits antral motor activity, delays gastric emptying and relaxes the gastric fundus. The aim of this study was to characterize the effect of sumatriptan on transpyloric flow and gastric accommodation during and immediately after ingestion of a liquid meal using duplex sonography. Ten healthy subjects were investigated twice on separate days. In random order either sumatriptan 6 mg (Imigran® 0.5 mL) or a placebo were given s.c. 15 min before ingesting 500 mL of a meat soup. The subjects were examined during the 3-min period before ingestion of the liquid meal, the 3-min spent drinking the meal and 10 min postprandially. Sumatriptan caused a significant widening of both the gastric antrum (P=0.02) and the proximal stomach (P=0.01) 10 min postprandially as compared with placebo. It caused no significant differences in time to initial gastric emptying (P=0.2), but significantly delayed commencement of peristaltic-related transpyloric flow (P=0.04). Sumatriptan had no significant effect on mean abdominal symptom scores, but after sumatriptan there was a significant negative correlation between width of postprandial antral area and postprandial nausea and between width of postprandial antral area and postprandial bloating. We therefore conclude that sumatriptan causes a postprandial dilatation of both the distal and the proximal stomach with no change in dyspeptic symptoms nor in length of time to first gastric emptying. Time to commencement of peristaltic-related emptying is delayed.     

5-HT receptor subtypes involved in the stimulatory effect of 5-HT on the peristaltic reflex in vitro

The effect of serotonin (5-HT) and of more selective 5-HT agonists on the peristaltic reflex evoked in the isolated guinea-pig ileum was investigated. Using the Trendelenburg technique, peristaltic contractions were elicited by increasing intraluminal pressure, and rhythmic contractions of the longitudinal and circular muscle were measured after serosal administration of the drugs. 5-HT potently stimulated contractions of the longitudinal muscle. The effect of 5-HT was partly antagonized by the 5-HT₄ receptor antagonist SDZ 205–557. Of the potent 5-HT_1A receptor agonists, 8-OH-DPAT, 5-carboxamidotryptamine (5-CT) and dipropyl-5-CT (DP-5-CT), only 5-CT caused a substantial stimulation. Of the 5-HT_1C-/5-HT₂ receptor agonists DOI and 5-methoxytryptamine (5-MeOT), DOI was inactive, whereas 5-MeOT potently stimulated contractions. 5-HT_1D receptor agonists (5-CT₁ sumatriptan) had a stimulatory effect. The effect of sumatriptan was antagonized by the 5-HT_1D receptor antagonist metitepine but not by the 5-HT₄ receptor antagonist SDZ 205–557. The 5-HT₃ receptor agonist 2-methyl-5-HT and the antagonists ICS 205–930 and granisetron did not influence the peristaltic reflex. 6-OH-indalpine, a 5-HT_1P agonist, was inactive. This data suggest that 5-HT stimulates the peristaltic reflex in the isolated guinea-pig ileum by activation of 5-HT₄- and 5-HT_1D receptors; other 5-HT receptor subtypes appear not to play a significant role in the modulation of this reflex.     

Heterogeneous effects of serotonin in the dorsal horn of rat: the involvement of 5-HT1 receptor subtypes

The effect of ionophoretically applied serotonin (5-HT) was tested on cutaneous sensory responses of multireceptive dorsal horn neurones in the anaesthetized rat. Three types of 5-HT action were discerned: selective inhibition of nociceptive responses (10/18 cells), non-selective inhibition of responses to both noxious and innocuous stimuli as well as to excitatory amino acids (4/18 cells) and non-selective excitation of evoked responses (1/18 cells). A few cells (3/18) were unaffected by 5-HT. The use of agonists, shown to discriminate between subtypes of 5-HT1 receptor revealed that a 5-HT1A receptor agonist mimicked the non-selective effects of 5-HT, whereas a 5-HT1B receptor agonist mimicked the selective antinociceptive effects of 5-HT. A 5-HT2 receptor agonist, in contrast, was without effect. Both the selective and the non-selective effects were reversed by a 5-HT1 receptor antagonist, but not a 5-HT2 antagonist.     

Heterogenous effects of serotonin in the dorsal horn of rat: the involvement of 5-HT1 receptor subtypes

The effect of ionophoretically applied serotonin (5-HT) was tested on cutaneous sensory responses of multireceptive dorsal horn neurones in the anaesthetized rat. Three types of 5-HT action were discerned: selective inhibition of nociceptive responses (10/18 cells), non-selective inhibition of responses to both noxious and innocous stimuli as well as to excitatory amino acids (4/18 cells) and non-selective excitation of evoked responses (1/18 cells). A few cells (3/18) were unaffected by 5-HT. The use of agonists, shown to discriminate between subtypes of 5-HT₁ receptor revealed that a 5-HT_1A receptor agonist mimicked the non-selective effects of 5-HT, whereas a 5-HT_1B receptor agonist mimicked the selective antinociptive effects of 5-HT. A 5-HT₂ receptor agonist, in contrast, was without effect. Both the selective and the non-selective effects were reversed by a 5-HT₁ receptor antagonist, but not a 5-HT₂ antagonist.     

Spinal cord injury-specific depression of monosynaptic spinal reflex transmission by l-5-hydroxytryptophan results from loss of the 5-HT uptake system and not 5-HT receptor supersensitivity

We studied changes in the spinal segmental reflex and serotonergic (5-HT) responses in rats after spinal cord injury (SCI) produced by the weight-dropping method at the T8 level. The spinal monosynaptic reflex amplitude (MSR) was recorded from the L5 ventral root following stimulation of the ipsilateral L5 dorsal root. The 5-HT precursor l-5-hydroxytryptophan (L-5-HTP) depressed MSR in the spinal cord injured rats but not in normal rats. We investigated whether the SCI-specific depression of MSR by L-5-HTP was attributable to postsynaptic supersensitivity of 5-HT receptors or presynaptic loss of the 5-HT uptake system. Sumatriptan, a selective 5-HT(1B/1D) receptor agonist that is not taken up by 5-HT transporters, depressed the MSR similarly in both SCI and normal rats, suggesting that SCI resulted in the loss of 5-HT terminals and not postsynaptic supersensitivity of 5-HT receptors.