Spinal Serotonin Research Articles

Supersensitivity to intrathecal 5-hydroxytryptamine, but not noradrenaline, following depletion of spinal 5-hydroxytryptamine by 5,7-dihydroxytryptamine administered into various sites

The present study was conducted (a) to determine if cross-supersensitivity at spinal noradrenergic receptors could be demonstrated in antinociceptive tests following depletion of spinal cord 5-hydroxytryptamine (5HT) by the intrathecal (i.t.) and intracerebroventricular (i.c.v.) administration of 5,7-dihydroxytryptamine (5,7DHT), and (b) to compare the pattern of supersensitivity at spinal 5HT receptors following these manipulations and 5,7DHT microinjected into the ventral raphe (VR) region and the nucleus raphe magnus (NRM). Both i.t. and i.c.v. administration of 5,7DHT produced a marked depletion of spinal cord 5HT (greater than 75%) and supersensitivity to the i.t. injection of 5HT in the tail flick and hot plate tests. No supersensitivity to the i.t. injection of noradrenaline (NA) was observed. Microinjection of 5,7DHT into the VR and NRM produced less depletion of spinal cord 5HT (40-57%), and supersensitivity to the i.t. injection of 5HT was observed only in the hot plate test following microinjection of 5,7DHT into the VR. An increased incidence of signs of the 5HT behavioural syndrome, particularly tremor and Straub tail, was observed in all 5,7DHT-pretreated groups. These results indicate that cross-supersensitivity to spinal NA receptors does not occur following depletion of spinal cord 5HT. In addition, responses mediated by 5HT receptors show a differential pattern of development of supersensitivity. Thus, the 5HT behavioural syndrome (presumably mediated by 5HT1A receptors) more readily reflects the development of supersensitivity than the tail flick test (presumably mediated by 5HT2 receptors), while the hot plate test (uncharacterized subtype) shows an intermediate development of supersensitivity.

Formalin nociception in the mouse does not lead to increased spinal serotonin turnover

The mouse formalin test is a model of tonic (continuous), chemical/inflammatory nociception. To test the hypothesis that bulbospinal serotonergic pathways modulate such nociception, whole spinal cords from mice pretreated with probenecid and sacrificed at 15, 30, 45 and 60 min after injection of 5% formalin or 0.9% saline in the hindpaw were assayed by high performance liquid chromatography with electrochemical detection for the serotonin metabolite, 5-hydroxyindoleacetic acid, as an index of turnover. No difference in serotonin turnover was found between formalin and saline groups, indicating that increased spinal serotonin release is not a normal response to formalin nociception in the mouse.

A comparative analysis of monoaminergic involvement in the spinal antinociceptive action of DAMPGO and DPDPE

The antinociceptive properties of intrathecally (i.t.) administered [ d-Ala 2, N-methyl-Phe 4,Gly 5-ol]enkephalin (DAMPGO) and [ d-Pen 2, d-Pen 5]enkephalin (DPDPE), selective opioid agonists for mu (μ) and delta (δ) sites, respectively, were compared in rats. DAMPGO and DPDPE elevated tail-flick latency (TFL) in a dose-dependent manner, and the spinal antinociceptive actions of both drugs were reversed by the opiate antagonist naloxone. These findings suggest that both DAMPGO and DPDPE interact with spinal opiate receptors to elevate TFL. Another set of experiments was done to determine the involvement of local spinal serotonin (5-HT) or norepinephrine (NE) in DAMPGO and DPDPE-induced spinal analgesia. Both the α 1 noradrenergic receptor antagonist WB-4101 and the α 2 blocker yohimbine failed to alter the antinociceptive actions of DAMPGO and DPDPE. Similarly, the 5-HT receptor antagonists pindolol, ritanserin and ICS 205–930 (selective for 5-HT 1, 5-HT 2 and 5-HT 3 sites, respectively) failed to inhibit opioid-induced spinal analgesia. Thus, while DAMPGO and DPDPE produce antinociception via an interaction with spinal opioid receptors, apparently neither drug activates endogenous monoaminergic systems.

Apparent hyperalgesia after lesions of the descending serotonergic pathways is due to increased tail skin temperature

It has been suggested that the descending serotonergic pathways exercise a tonic inhibition on nociception in the spinal cord. In this study 5,6-dihydroxytryptamine (5,6-DHT, 20 μg base) injected intrathecally in rats reduced spinal serotonin concentration to 3.5% of control levels without significantly affecting spinal noradrenaline. The lesion reduced the mean tail-flick latency by approximately 35% and increased the mean tail skin temperature by approximately 3.5°C; both parameters gradually returned to normal values within 2–3 weeks. Both in controls and in lesioned animals there was a highly significant negative correlation between tail skin temperature and tail-flick latency. Multiple regression analysis showed that the effect of lesioning on tail-flick latency was non-significant when the effect of skin temperature was taken into account. Thus the reduced tail-flick latency after lesions of descending serotonergic pathways, usually interpreted as increased nociception, may be due to changes in tail skin temperature.

The antinociceptive role of a bulbospinal serotonergic pathway in the rat brain

The antinociceptive role of spinal serotonin (5-HT) neurons descending from 5-HT cells near the ventrolateral surface of the medulla oblongata was investigated by stimulating these cells in normal rats, in rats with generalized or selective chemical ablation of 5-HT nerves, and in rats with postsynaptic blockade of 5-HT receptors. Electrical stimulation of the lateral medulla elicited analgesia in normal rats; the increase in pain threshold was proportional to the intensity and to the frequency of stimulation. In addition, microinjection of kainic acid or l-glutamate at the same sites also produced analgesia. However, generalized destruction of CNS 5-HT nerves produced by intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) or selective destruction of spinal 5-HT nerves produced by intraspinal injection of 5,7-DHT reduced the magnitude of the antinociceptive responses to electrical stimulation. Postsynaptic blockade of CNS 5-HT receptors produced by intraventricular injection of cyproheptadine also reduced the stimulation-produced analgesia. The specificity of the lesions for 5-HT nerves is demonstrated by the lack of effect on the levels of noradrenaline in the same brain regions. The results indicate that the activity of 5-HT nerve cells adjacent to the ventrolateral surface of the medulla oblongata and projecting to the spinal cord serves to elevate pain threshold.

Effects of Intrathecal Administration of Methysergide, Phentolamine, and Pindolol on Pressor Responses to Electrical Stimulation of the Rostral Ventrolateral Medulla

Neurons projecting from the rostral ventrolateral medulla (RVLM) to the spinal cord are important in blood pressure control. The present experiments examined the role of spinal adrenoreceptors and serotonin receptors in mediating the pressor effects of electrical stimulation of the RVLM. Accordingly the effects on blood pressure of electrical stimulation of the RVLM were studied before and after intrathecal administration of adrenergic or serotonergic antagonists in normotensive and hypertensive rats. Electrical stimulation in the area of the RVLM-B3 serotonin-containing neurons in Wistar-Kyoto (WKY) rats increased blood pressure, and the pressor responses were reduced by intrathecal methysergide (30 and 100 micrograms). Similar findings were seen in spontaneously hypertensive rats (SHR). In WKY, electrical stimulation in the area of the RVLM-C1 epinephrine-containing neurons, increased mean arterial pressure (MAP), but the pressor responses were unaffected by intrathecal phentolamine (15 micrograms), pindolol (2 micrograms), or methysergide (30 and 100 micrograms), or saline. The results suggest that the pressor effects of stimulation of the RVLM-B3 area are mediated at least in part through activation of spinal serotonin receptors. The lack of effect of phentolamine and pindolol on the RVLM-C1 area pressor responses raises a question regarding the importance of spinal adrenergic receptors in mediating these effects.

The somatosensory evoked potential predicts neurologic deficits and serotonergic pathochemistry after spinal distraction injury in experimental scoliosis.

The validity of the somatosensory evoked potential as an intraoperative spinal cord monitor was evaluated in an experimental model of scoliosis in the rat and a Harrington distraction model of injury. Under these conditions, it was found that any change in latency or amplitude of the major negative wave above a certain level was a significant predictor of an adverse neurologic outcome. Changes in latency of 4% or greater and changes in amplitude of 50% or greater were unequivocal indicators of spinal cord injury. Postmortem analyses of the spinal neurotransmitter serotonin revealed that apparent false-positive results of the SEP were, in fact, true-positive results.

A spinal projection of 5-hydroxytryptamine neurons in the lamprey brainstem; evidence from combined retrograde tracing and immunohistochemistry

To investigate whether there is a descending contribution to the spinal 5-hydroxytryptamine (5-HT) innervation in the lamprey, a primitive vertebrate, a study using retrograde transport of the fluorescent tracer Fast blue combined with 5-HT immunohistochemistry was conducted. Two to 4 weeks after an injection of Fast blue into the rostral spinal cord, retrogradely labelled cells were seen throughout the brainstem. Two groups of these cells, one within the posterior reticular nucleus of the rhombencephalon and another rostral to the trigeminal motor nucleus, were labelled after incubation with 5-HT antiserum. These findings suggest that in addition to the well-described local intraspinal 5-HT system, there is also, as in higher vertebrates, a descending 5-HT projection from the brainstem which extends at least 20 segments into the spinal cord.

Studies on the separate roles of forebrain and spinal serotonin in morphine analgesia.

5,7-Dihydroxytryptamine (5,7-DHT) injections in the ventromedial tegmentum (VMT) at the level of nucleus interpeduncularis or in the ventral raphe area (VR) of the medulla oblongata were used to study the separate roles of forebrain and spinal 5-HT in the antinociceptive effect of morphine in rats. 5,7-DHT injections in the VMT, which caused marked, selective depletion of forebrain 5-HT, did not modify the effect of morphine in the hot plate and tail immersion tests. Direct injection of 5,7-DHT into the nucleus raphe medianus also failed to modify the effect of morphine in the two tests used to measure nociceptive responses. The effect of morphine was significantly reduced 30 min after injection to rats depleted of spinal 5-HT by 5,7-DHT injected in the VR but the areas under the curves between vehicle and 5,7-DHT treated animals were not significantly different. The data show that the integrity of 5-HT neurons in the forebrain is not necessary for the antinociceptive effect of morphine and a substantial amount of this effect is still present in rats with marked depletion of spinal 5-HT.

II. Examination of spinal monoamine receptors through which brainstem opiate-sensitive systems act in the rat

The microinjection through stereotaxically implanted guide cannulae of morphine (5 μg/0.5 μl) into the periaqueductal gray, the n. raphe magnus or the n. reticulogigantocellularis results in a significant elevation in the latency of a thermally evoked, spinally mediated reflex (tail-flick) and a supraspinally organized response (hot-plate). Spinal serotonin, noradrenalin, opiate and dopamine receptors were antagonized by the injection through chronically implanted intrathecal catheters of methysergide, phentolamine, naloxone and cis-flupenthixol, respectively. After a significant elevation of the tail-flick response latencies with intracerebral injections of morphine into the periaqueductal gray, the magnitude of the reversal produced by the intrathecally administered antagonists was phentolamine=methysergide≫naloxone=cis-flupenthixol= 0. After a significant elevation of the tail-flick response latency with intracerebral injections of morphine into the n. raphe magnus, the magnitude of the reversal produced by the intrathecally administered antagonist was methysergide>phentolamine>naloxone≫cis-flupenthixol= 0. After a significant elevation of the tail-flick response latency was produced by the microinjection of morphine into the n. reticulogigantocellularis, the magnitude of the reversal produced by intrathecal antagonists was phentolamine>naloxone≫methysergide=cis-flupenthixol= 0. None of the intrathecal antagonists reversed the elevation of the hot-plate response latencies produced by morphine injections into the n. raphe magnus and n. reticulogigantocellularis injections. A significant, but clearly subtotal reversal of the elevated hot-plate response latencies produced by periaqueductal gray morphine was produced by intrathecal phentolamine and methysergide. It is concluded that discrete populations of brain opiate receptors in the periaqueductal gray, n. raphe magnus and n. reticulogigantocellularis differentially activate spinal monoamine and opioid receptors to modulate thermally evoked spinally mediated reflexes. The general failure of treatments which reverse the segmental reflex inhibition to reverse the hot-plate effects suggests that: (1) other spinopetal pathways are operative; (2) that descending pathways activated by these manipulations do not contribute to the analgesic effects of brainstem morphine; and/or (3) that in addition to spinopetal modulation, brainstem opiate receptors modulate nociceptive transmission at the brainstem level.

Spinal mechanisms of te analgesic action of electroconvulsive shock

The present study investigated the spinal systems involved in the analgesic action of electroconvulsive shock (ECS). To identify such systems complete spinal transections and discrete lesions within the dorsal half of the spinal cord were performed. Complete spinal transection eliminated ECS analgesia totally, demonstrating that the observed analgesic effect is attributable to neural conduction. Lesions within the region of the dorsolateral funiculus (DLF) caused a pronounced, but incomplete, attenuation of ECS analgesia. Larger lesions of the dorsal aspects of the spinal cord including both the DLF and the dorsal column area did not result in further attenuation of analgesia. Thus, it appears that within the dorsal cord the area of the DLF contains the fibers mediating the antinociceptive action of ECS. Additional experiments were conducted to determine the neuromediators involved in ECS analgesia. Of a wide range of antagonists injected intraperitoneally (methysergide, phentolamine, haloperidol, diphenhydramine, naloxone, picrotoxin, theophylline and scopolamine), only methysergide produced a significant attenuation of ECS analgesia. In contrast, following intrathecal injections of antagonists a dose-related decrease of analgesia could be seen after the injection of methysergide, phentolamine and naloxone implicating spinal serotonin, noradrenaline and the enkephalins in the analgesic action of ECS. To assess further the interaction between the action of these neurotransmitter systems, we evaluated the effect of drug pair combinations on ECS analgesia. Intrathecal phentolamine + naloxone, methysergide + naloxone and methysergide + phentolamine were injected at doses that caused maximal attenuation of analgesia. Injections of drug combinations did not result in further attenuation of ECS analgesia. It appears that the analgesic action of ECS is mediated via systems descending within the spinal cord. The main contribution to the analgesic action of ECS is from fibers coursing within the DLF, although contribution of neural systems within the ventral spinal cord also exists. These descending analgesia systems appear to utilize serotonin, noradrenaline and endogenous opioids as neurotransmitters. Additional systems the pharmacological nature of which is still undetermined also exist.

Topographic principles in the spinal projections of serotonergic and non-serotonergic brainstem neurons in the rat

The spinal projections from the raphe-associated brainstem areas containing serotonergic neurons were studied with aldehyde-induced fluorescence in combination with the retrograde fluorescent tracer True Blue in the rat. This technique makes it possible to determine simultaneously the projections of individual neurons and to detect whether serotonin is present in the same neurons. After tracer injections into the spinal cord retrogradely labeled serotonergic and non-serotonergic neurons were found in the medullary raphe nuclei and adjacent regions and to a lesser extent in association with the dorsal and median raphe nuclei in the mesencephalon. Large True Blue injections that covered one side of the spinal cord at mid-cervical level labeled about 60% of the ipsilaterally situated serotonergic neurons in the medullary raphe regions while the corresonding figure contralaterally was about 25%. On both sides a larger number of labeled non-serotonergic neurons were found; these were sometimes located dorsal to, but often intermingled with, the serotonergic cells. While the serotonergic projection from the mesencephalon could not be labeled from injections below cervical levels, the labeling in more caudal brainstem regions exhibited only minor variations depending on the rostrocaudal level of the spinal segment injected. Furthermore, quantitative data from injections at different levels indicate that the majority of the spinal-projecting neurons traverse most of the length of the cord. Summarizing the results obtained from small injections restricted to subregions of the cord we feel that it is possible to distinguish three fairly distinct pathways for spinal projections from the medullary raphe and adjacent regions: (1) The dorsal pathway originates mainly from cells in the caudal pons and rostral medulla oblongata (rostral part of nucleus raphe magnus, nucleus raphe magnus proper, nucleus reticularis gigantocellularis pars α and nucleus paragigantocellularis). This pathway, which contains a large non-serotonergic component, descends through the dorsal part of the lateral funiculus and terminates mainly in the dorsal horn at all spinal cord levels. (2) The intermediate pathway is largely serotonergic with its cell bodies located within the arcuate cell group (situated just ventral and lateral to the pyramids very close to the ventral surface of the brainstem) and in the nucleus raphe obscurus and pallidus and terminates in the intermediate grey at thoracolumbar and upper sacral levels. (3) The ventral pathway consists of serotonergic and non-serotonergic axons descending in the ventral white matter to terminate in ventral horn areas along the entire length of the cord. These axons originate mainly from neurons in the caudal medulla (nucleus raphe obscurus and pallidus and nucleus reticularis ventralis). This study shows that from all brainstem regions which gave rise to spinal serotonin projections there also exist (often larger) non-serotonergic spinal projections. While the serotonergic systems are highly topographically arranged the non-serotonergic projection (taken as a whole) is more diffusely arranged.

Central noradrenergic involvement in yohimbine excitation of acoustic startle: Effects of DSP4 and 6-OHDA

It was previously shown that i.p. administration of the a 2-adrenergic antagonists yohimbine increased the magnitude of the acoustic startle response in rats 11. The purpose of the present study was to determine possible central noradrenergic involvement in yohimbine's effect on startle. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromo-benzylamine (DSP4; 50 mg/kg, i.p.; 1–2 days before testing) completely blocked the excitatory effect of yohimbine on startle. DSP4 reduced forebrain and spinal cord NE levels with the and 56%, respectively, without affecting forebrain or spinal serotonin (5-HT), or forebrain dopamine (DA). Pretreatment with the NE reuptake blocker desmethylimipramine (DMI; 20 mg/kg, i.p.; 30 min before DSP4) prevented the ability of DSP4 to block the yohimbine effect. DMI partially reversed the NE-depleting effects of DSP4. Neither bilateral adrenalectomy nor intravenously administered 6-hydroxydopamine (6-OHDA; 20 mg/kg; 1–2 days before testing) altered the excitatory of yohimbine, indicating that peripheral NE is not involved. 6-OHDA (2 × 200 μg) injected into the lateral ventricles blocked yohimbine's effect, and depleted NE by 95% (spinal cord) adn 86% (forebrain), without affecting 5-HT in either region. 6-OHDA also depleted forebrain DA levels by 49%. Finally, intrathecal administration of 6-OHDA (20 μg; 14 days before testing) into the subarachnoid space of the lumbar spinal cord blocked the excitatory effect of yohimbine, and produced an extensive (94%) depletion of spinal cord NE. Intrathecal 6-OHDA did not alter spinal levels of 5-HT or forebrain levels of NE, 5-HT or DA. In summary, these data indicate that central descending NE neurons are necessary for yohimbine's excitatory effect on startle.

In vivo evaluation of mu, delta and kappa opioid receptor agonists on spinal 5-HT metabolism in the rat

Morphine was found to elevate spinal dorsal horn 5-hydroxyindole acetic acid (5-HIAA) in a dose-dependent manner. These actions also were naloxone-reversible. In marked contrast other mu, delta and kappa opioid receptor agonists did not alter 5-HIAA levels. These studies clearly indicate that descending spinal 5-hydroxytryptamine (5-HT) pathways are not essential for opiate analgesia.

Test-dependent antinociceptive effect of spinal serotonin release induced by intrathecal p-chloroamphetamine in mice.

The effect of direct intrathecal injection of p-chloroamphetamine (PCA) into the lumbar subarachnoid space was investigated in mice. PCA (0.6 - 20 micrograms) induced a dose-related prolongation of response latencies in the tail-flick test, but failed to affect the hind-paw lick response in a hot-plate test employing slowly rising temperature. PCA (5 micrograms) given intracerebroventricularly did, however, significantly elevate the response temperature in the hot-plate test. The antinociceptive effect of PCA in the tail-flick test was prevented by spinalization, by pretreatment with the selective serotonergic re-uptake blocker zimelidine (20 mg X kg-1 i.p.) and by the serotonin synthesis inhibitor p-chlorophenylalanine (300 + 300 + 150 mg X kg-1 i.p. 72, 48 and 24 h before test). It is concluded that PCA given intrathecally releases serotonin from spinal terminals, which may under certain conditions induce antinociception.

The neurochemical basis of footshock analgesia: the role of spinal cord serotonin and norepinephrine

Previous studies have demonstrated that brief front paw and brief hind paw shock produce potent opiate and non-opiate analgesia, respectively. Additionally, opiate analgesia can be classically conditioned by using either front paw shock or hind paw shock as the unconditioned stimulus. Front paw footshock-induced analgesia (FSIA), hind paw FSIA, and classically conditioned analgesia are similar in that each is mediated by a medullospinal pathway. However, the neurochemistry of these medullospinal connections has never been investigated. One question which arises is whether any of these phenomena are mediated by monoaminergic neurotransmitters at the level of the spinal cord. The present series of experiments examined the effect of depleting spinal serotonin (5-HT) and combined depletion of spinal 5-HT and norepinephrine (NE) on front paw FSIA, hind paw FSIA, and classically conditioned analgesia. Hind paw FSIA and classically conditioned analgesia were not attenuated by either of these neurochemical manipulations. Front paw FSIA was significantly reduced by both 5-HT depletion and combined 5-HT and NE depletion. To assess the relative importance of spinal 5 HT and NE in front paw FSIA, NE and 5-HT antagonists were injected onto the lumbosacral cord prior to shock exposure. Attenuation of front paw FSIA by equimolar doses of the monoamine blockers was much greater following injection of the 5-HT blocker than after the NE blocker. These data indicate that spinal 5-HT and, apparently to a lesser extent, spinal NE mediate front paw (opiate) FSIA whereas neither 5-HT nor NE appears to mediate hind paw FSIA or classically conditioned analgesia.

Selective lesions of the bulbospinal serotonergic pathways reduce the analygesia induced by p-chloroamphetamine in the hot-plate test

The antinociceptive effect of the serotonin releasing compound p-chloroamphetamine (PCA) was investigated in rats by means of the hot-plate method. Selective neurotoxic lesions of the descending serotonergic pathways induced by intrathecal injections of 5,6-dihydroxytryptamine (20 μg, 7 days before testing), produced hyperalgesia and significantly attenuated the analgesic effect of acutely administered PCA (2.5 mg/kg). The lesions reduced the spinal serotonin content by about 90% without significantly altering noradrenaline levels. It is concluded that the descending serotonergic pathways contribute to the expression of PCA-induced hot-plate analgesia.

Evidence for a bulbospinal serotonergic pressor pathway in the rat brain

The cardiovascular role of spinal serotonin (5-HT) neurones descending from 5-HT cells near the ventrolateral surface of the medulla oblongata was investigated by stimulating these cells in normal animals and in animals with selective chemical ablation of 5-HT nerves. These laterally placed 5-HT nerves fall within the B1 and B3 groups in the medulla and were identified using immunohistochemistry. 5,7-Dihydroxytryptamine (5,7-DHT) was injected into the lateral cerebral ventricle (i.c.v.) to produce a generalized destruction of central 5-HT pathways, with preliminary intraperitoneal administration of desipramine to prevent depletion of noradrenaline stores. In other experiments, 5,7-DHT was injected directly into the cervical spinal cord, after preliminary treatment with desipramine, to produce selective destruction of spinal 5-HT nerves, confirmed both biochemically and immunohistochemically. Electrical stimulation near the lateral 5-HT cells in the B1 and B3 cell groups elicited pressor responses in control (vehicle-injected) rats; the increase in mean arterial pressure was proportional to the intensity and to the frequency of stimulation. Microinjections of kainic acid or l-glutamate at the same sites also produced an increase in mean arterial pressure. Selective destruction of 5-HT nerves, whether produced by i.c.v. or intra-spinal administration of 5,7-DHT, reduced the magnitude of the pressor response to electrical stimulation by over 50%. These experiments suggest the activity of 5-HT nerve cells adjacent to the ventrolateral surface of the medulla oblongata and projecting to the intermediolateral cell column serves to elevate arterial pressure and maintain vasomotor tone.

Studies on the role of serotonin in different regions of the rat central nervous system on pentylenetetrazol-induced seizures and the effect of di-n-propylacetate.

5,7-Dihydroxytryptamine (5,7-DHT) injections which caused selective depletion of serotonin in the forebrain enhanced the seizures caused by pentylenetetrazol (PTZ 90 mg/kg s.c.) in rats. No effect was observed in rats with 5,7-DHT-induced depletion of spinal serotonin or treated with metergoline (1 mg/kg i.p.) or methysergide (10 mg/kg i.p.). The various procedures aimed at decreasing serotonin transmission did not significantly modify the effect of di-n-propylacetate (DPA) on tonic seizures and mortality caused by PTZ but significantly reduced the DPA-induced increase in the latency to the first convulsion. More animals with clonic seizures were seen in the DPA-treated group which had been subjected to selective depletion of spinal serotonin or treated with methysergide than in DPA-treated controls. Combined treatment with d-fenfluramine (1.25 mg/kg i.p.) and DPA (75 mg/kg i.p.), doses which by themselves had no significant effect, reduced tonic seizures and mortality caused by PTZ. The results show that a diffuse deficit in forebrain serotonin enhances PTZ-induced seizures. Serotonin does not play an important role in the effect of DPA against PTZ-DPA on clonic convulsions. Agents increasing serotonin transmission may enhance the anticonvulsant activity of DPA.

Neonatal intraspinal 6-hydroxydopamine, 5,7-dihydroxytryptamine or their combination: Effects on nociception and morphine analgesia

Newborn rats received two injections of intraspinal 6-hydroxydopamine (6-OHDA, 10 μg) or 5,7-dihydroxytryptamine (5,7-DHT, 8 μg preceded by s.c. desmethylimipramine) or a ‘cocktail’ of both neurotoxins. The two injections were separated by 24 h. When assayed in adulthood, the 6-OHDA rats showed a substantial (about 80%) depletion of spinal norepinephrine (NE) but an elevation of brainstem NE. Conversely, the 5,7-DHT rats showed a modest (about 60%) loss of spinal serotonin (5-HT) but an elevation of brainstem 5-HT. Rats receiving combined 6-OHDA plus 5,7-DHT showed rostro-caudal, decreasing gradients of spinal NE and 5-HT depletions, with the largest loss in the lumbar cord. These depletions were much less than those observed after the respective single neurotoxin treatments. Neither the single nor combined neurotoxin treatments altered the tail-flick analgesia induced by morphine (1.0, 3.0 or 7.5 mg/kg s.c.). Basal nociception, however, was altered by the neurotoxins but in a sexually dimorphic manner. The 6-OHDA lowered baseline tail-flick latencies in females while 5,7-DHT elevated latencies in males. Like the 6-OHDA-only rats, the combined 6-OHDA plus 5,7-DHT lowered latencies in females. We conclude that neither spinal NE nor 5-HT are essential to morphine analgesia but do participate in nociception, seemingly in a sexually dimorphic fashion.