Administration Of Methysergide Research Articles

Spinal mechanisms of pudendal nerve stimulation-induced inhibition of bladder hypersensitivity in rats

Bilateral electrical pudendal nerve stimulation (bPNS) reduces bladder hypersensitivity in rat models of bladder pain and anecdotally reduces pain in humans with pelvic pain of urologic origin. The spinal neurochemical mechanisms of this antinociception are unknown. In the present study, bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Visceromotor responses (VMRs; abdominal muscle contractions) to urinary bladder distension (UBD) were used as a nociceptive endpoint under urethane-isoflurane anesthesia. bPNS consisted of bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Following determination of the inhibitory effect of bPNS on VMRs, pharmacological antagonists were administered via an intrathecal catheter onto the lumbosacral spinal cord and bPNS effects on VMRs redetermined. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that was statistically reduced by the intrathecal administration of methysergide, WAY100636, CGP35348 and strychnine but was unaffected by naloxone, bicuculline, phentolamine, ondansetron and normal saline. This study suggests that inhibitory effects of bPNS may include serotonergic, GABA-B-ergic and glycinergic mechanisms suggesting the potential for interaction of the neuromodulatory effect with concommitant drug therapies.

Nanoemulsion Thermoreversible Pluronic F127-Based Hydrogel Containing Hyptis pectinata (Lamiaceae) Leaf Essential Oil Produced a Lasting Anti-hyperalgesic Effect in Chronic Noninflammatory Widespread Pain in Mice.

We evaluated if a nanostructured thermoreversible Pluronic F127-based hydrogel incorporated with Hyptis pectinata leaf essential oil (NE-EOH) produces a long-lasting anti-hyperalgesic effect on chronic muscle pain in an animal model. We induced chronic muscle pain by injecting the gastrocnemius with saline injections. Paw and muscle withdrawal thresholds and motor performance were evaluated after treatment and compared with morphine, diazepam, or vehicle. Naloxone and methysergide administration tested the involvement of opioid and serotonin receptors, respectively. Sites of action in the central nervous system for the NE-EOH were examined by measuring substance P (SP) levels in the spinal cord and Fos protein in the brainstem. NE-EOH increased paw and muscle withdrawal thresholds when compared with vehicle but had no effect on motor function. This analgesic effect was reversed by both naloxone and methysergide. NE-EOH decreased elevated substance P levels and reduced Fos-labeled neurons in the spinal cord and increased the number of Fos-labeled neurons in the periaqueductal gray (PAG), nucleus raphe magnus (NRM), and locus coeruleus (LC). NE-EOH was shown to produce a lasting anti-hyperalgesic effect. It uses opioid and serotonin receptors, activates brainstem inhibitory pathways, and reduces the release of excitatory neurotransmitters in the spinal cord and is a substance with potential to be used in the treatment of noninflammatory pain conditions. Graphical Abstract.

Methysergide attenuates systemic burn edema in rats

BackgroundThermal injuries of more than 20% total body surface area result in systemic shock with generalized edema. Burn shock is induced by a variety of mediators, mainly immunomodulative cytokines. Administration of methysergide (Met), a serotoninergic receptor blocking agent, reduces generalized edema in endotoxemia in rats. In this study we evaluated the systemic effects of Met after thermal injury. MethodsDonor rats (DR [n=8]) for positive controls and study groups underwent thermal injury (100°C water, 30% TBSA (Total Burn Surface Area), 12s). Shamburn plasma was harvested after a shamburn procedure ([n=4], 37°C water, 30% TBSA, 12s). Plasma was harvested 4h posttrauma and was transferred to healthy individuals. Recipient animals were randomized in 3 groups (1: burnplasma, 2: shamburn, 3: burnplasma plus methysergide (Bolus of 1mg/kg body weight)). Intravital microscopy was performed in mesenteric venules (0/60/120min). Edema was assessed by FITC-albumin extravasation. Leukocyte sticking (cells/mm2) and microhemodynamic parameters were assessed. ResultsSignificant systemic capillary leakage was observed after burnplasma-transfer. Edema formation was significantly lower in negative controls. Application of methysergide reduced FITC-efflux to baseline levels. Adherent leukocytes increased in all groups, at 120min the amount of adherent leukocytes in positive controls was significantly higher in comparison to shamburn, differences to MET-groups were not significant. ConclusionBurnplasma transfer to healthy individuals induces leukocyte activation and plasma extravasation and this effect is reduced by administration of Met. This may be attributed to leukocyte dependent as well as independent mechanisms. Evaluation of more specific serotoninergic antagonists is required to distinguish between systemic and local effects.

Effects of milnacipran, a 5‐HT and noradrenaline reuptake inhibitor, on C‐fibre‐evoked field potentials in spinal long‐term potentiation and neuropathic pain

The analgesic action of 5-HT and noradrenaline reuptake inhibitors (SNRIs) on nociceptive synaptic transmission in the spinal cord is poorly understood. We investigated the effects of milnacipran, an SNRI, on C-fibre-evoked field potentials (FPs) in spinal long-term potentiation (LTP), a proposed synaptic mechanism of hypersensitivity, and on the FPs in a neuropathic pain model. C-fibre-evoked FPs by electrical stimulation of the sciatic nerve fibres were recorded in the spinal dorsal horn of anaesthetized adult rats, and LTP was induced by high-frequency stimulation of the sciatic nerve fibres. A rat model of neuropathic pain was produced by L5 spinal nerve ligation and transection. Milnacipran produced prolonged inhibition of C-fibre-evoked FPs when applied spinally after the establishment of LTP of C-fibre-evoked FPs in naïve animals. In the neuropathic pain model, spinal administration of milnacipran clearly reduced the basal C-fibre-evoked FPs. These inhibitory effects of milnacipran were blocked by spinal administration of methysergide, a 5-HT½ receptor antagonist, and yohimbine or idazoxan, α₂-adrenoceptor antagonists. However, spinal administration of milnacipran in naïve animals did not affect the basal C-fibre-evoked FPs and the induction of spinal LTP. Milnacipran inhibited C-fibre-mediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal LTP and in the neuropathic pain model, by activating both spinal 5-hydroxytryptaminergic and noradrenergic systems. The condition-dependent inhibition of the C-fibre-mediated transmission by milnacipran could provide novel evidence regarding the analgesic mechanisms of SNRIs in chronic pain.

Subarachnoid Serotonergic and Noradrenergic Antagonists increase the Pain Response in Rats

There is evidence that the passage of nociceptive information through the posterior horn of the spinal cord (PHSC) on its way to rostral levels of the central nervous system undergoes profound excitatory and inhibitory influences. The objective of the present study was to compare the effects of the subarachnoid administration of methysergide, phentolamine, and phentolamine associated with methysergide on phases I, intermediate, and II of the modified formalin test in rats. Twenty-eight male Wistar rats distributed randomly in four groups (n=7) to received subarachnoid saline solution (GC), phentolamine (GF), methysergide (GM), or phentolamine associated with methysergide (GFM). Pain was induced by the administration of formalin in the dorsal region of the right hind paw. The test was divided in three phases: phase I, intermediate, and phase II. Statistical analysis of the results was performed using the software SPSS (Statistical Package for Social Sciences), adopting a level of significance of 5%. In the intermediate phase the number of paw elevations was significantly higher in GF, GM, and GFM groups when compared to the GC group. The results suggest the existence of a noradrenergic and serotonergic effect in the inhibitory descending system of acute pain, with the possibility of using serotonergic and α1-adrenergic antagonists to control acute pain.

Genesis of gasping is independent of levels of serotonin in the Pet-1 knockout mouse

Eupnea is normal breathing. If eupnea fails, as in severe hypoxia or ischemia, gasping is recruited. Gasping can serve as a powerful mechanism for autoresuscitation. A failure of autoresuscitation has been proposed as a basis of the sudden infant death syndrome. In an in vitro preparation, endogenous serotonin is reported to be essential for expression of gasping. Using an in situ preparation of the Pet-1 knockout mouse, we evaluated such a critical role for serotonin. In this mouse, the number of serotonergic neurons is reduced by 85-90% compared with animals without this homozygous genetic defect. Despite this reduction in the number of serotonergic neurons, phrenic discharge in eupnea and gasping of Pet-1 knockout mice was not different from that of wild-type mice. Indeed, gasping continued unabated, even after administration of methysergide, a blocker of many types of receptors for serotonin, to Pet-1 knockout mice. We conclude that serotonin is not critical for expression of gasping. The proposal for such a critical role, on the basis of observations in the in vitro slice preparation, may reflect the minimal functional neuronal tissue and neurotransmitters in this preparation, such that the role of any remaining neurotransmitters is magnified. Also, rhythmic activity of the in vitro slice preparation has been characterized as eupnea or gasping solely on the basis of activity of the hypoglossal nerve or massed neuronal activities of the ventrolateral medulla. The accuracy of this method of classification has not been established.

Intrinsic neural circuits between dorsal midbrain neurons that control fear-induced responses and seizure activity and nuclei of the pain inhibitory system elaborating postictal antinociceptive processes: a functional neuroanatomical and neuropharmacological study

The blockade of GABA-mediated Cl − influx with pentylenetetrazol (PTZ) was used in the present work to induce seizures in Rattus norvegicus. The aim of this work was to study the involvement of monoamines in the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the postictal period. Peripheral administration of methysergide (0.5, 1, 2, and 3 mg/kg) caused a significant decrease in the TFL in seizing animals, as compared to controls, in all postictal periods studied. These findings were corroborated by the pretreatment with ketanserin, a 5-HT 2A/2C-serotonergic/α 1-noradrenergic receptors antagonist, at the same doses. Peripheral administration of yohimbine (0.5, 1, 2, and 3 mg/kg), α 2-noradrenergic antagonist, also decreased the postictal analgesia either at initial or more terminal periods of the postictal analgesia. These data were corroborated with peripheral administrations of propranolol, a β-noradrenergic receptor blocker that caused a decrease in the postictal analgesia consistently in later stages (after the first 20-min post-tonic-clonic convulsive reactions) of the postseizure analgesia, except for the highest dose. These results indicate that monoamines may be involved in the postictal analgesia. The blockade of 5-HT 2A/2C-serotoninergic, α 1-noradrenergic, or α 2-noradrenergic receptors before tonic clonic seizure-induced analgesia antagonized the increase in the nociceptive threshold caused by seizures in initial steps of the temporal antinociceptive curve, as compared to the blockade of β-noradrenergic ones. These findings suggest that the recruitment of α-noradrenergic receptor and serotonergic receptors was made immediately after convulsions and in other initial periods of the postictal analgesia, as compared to the involvement of β-noradrenergic receptor. Neurochemical lesions of the locus coeruleus (LC) and neuronal damage of the dorsal raphe nucleus induced a significant decrease of the postictal analgesia, suggesting the involvement of these nuclei in this antinociceptive process. The functional neuroanatomical study of the neural link between the mesencephalic tectum and nuclei of the central pain inhibitory system showed evidence for the interconnection between superior colliculus, both dorsal and ventral periaqueductal gray matter (PAG), and inferior colliculus. Defensive substrates of the inferior colliculus, also involved with wild running and epilepsy, send inputs toward dorsal raphe nucleus and locus coeruleus. Since these nuclei are rich in monoamines and send neural connections toward other monoaminergic nuclei of the brainstem involved with the control of the nociceptive inputs in the dorsal horn of the spinal cord, the present results offer a neuroanatomical and psychopharmacological basis for the antinociceptive processes following tonic-clonic seizures.

α 2-Adrenoceptors and 5-HT receptors mediate the antinociceptive effect of new pyrazolines, but not of dipyrone

In this study, we investigated whether spinal noradrenergic and serotonergic systems are involved in the antinociception induced by the novel pyrazolines 3-methyl- and 3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1 H-1-pyrazole-1-carboxyamide (MPCA and PPCA, respectively), and the pyrazolinone dipyrone in the acetic acid writhing (stretching) test in mice. Intrathecal (i.t.) administration of methysergide (3 and 10 μg) and yohimbine (3 μg), but not of prazosin (0.3 and 1 μg) prevented the antinociceptive action of MPCA and PPCA (500 μmol/kg, s.c.). Dipyrone-induced antinociception (500 μmol/kg, s.c.) was not affected by methysergide or adrenoceptor antagonists. These results suggest that spinal 5-HT receptors and α 2-adrenoceptors are involved in the antinociception induced by MPCA and PPCA, but not in that elicited by dipyrone.

Antinociceptive Effects of Methysergide in Various Pain Models

Several studies have demonstrated that the nonselective opioid receptor antagonist naloxone produces a paradoxical antinociception in the formalin test. The opioid system is related to the serotonergic system for producing antinociception at the spinal level. Here we also asked whether systemic (i.p.) and intrathecal (i.t.) administrations of a nonselective serotonergic antagonist, methysergide, might produce paradoxical antinocicpetion similar to naloxone in the mouse formalin test. A diluted formalin solution was injected into the mouse plantar region of the hind paw and the duration of licking responses was measured at periods of 0–5 min (1st phase) and 20–40 min (2nd phase) after formalin injection. Methysergide administered i.p. and i.t. showed an attenuated licking duration only in the 2nd phase. The effect observed in the 2nd phase was reversed in the 5,7-dihydroxytriptamine, but not N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated group of mice, suggesting that descending serotonergic, but not noradrenergic, systems are involved in the methysergide antinociception. To further investigate the mechanism by which methysergide inhibited the nociceptive behaviors induced by formalin, the antinociceptive effect of methysergide was also tested in substance P (i.t.) and excitatory amino acids (i.t.), such as glutamate, N-methyl-D-aspartic acid, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and kainic acid, which are major components in the formalin-induced nociceptive transmission in the spinal cord pain models. The duration of nociceptive behaviors shown in these models was significantly shortened by i.p. and i.t. administration of methysergide. These results suggest that methysergide also produces a paradoxical antinociception in various pain models including the formalin test, similar to the results of naloxone.

Response properties of neurons in the rostroventromedial medulla of neuropathic rats: attempted modulation of responses by [1DMe]NPYF, a neuropeptide FF analogue

We determined whether chronic neuropathy changes response properties of neurons in the rostroventromedial medulla of rats, and whether (d-Tyr)L(Me-Phe)QPQRF-amide, a neuropeptide FF analogue, in the periaqueductal gray produces changes in responses of rostroventromedial medullary neurons that might underlie its antiallodynic effect described earlier. Single unit recordings of medullary neurons were performed in lightly anesthetized neuropathic and control animals. Spontaneous activity and the responses to noxious thermal and mechanical stimulation of the hind paw were determined with and without administration of (d-Tyr)L(Me-Phe)QPQRF-amide. The neurons were classified into three groups: ON-neurons increased, OFF-neurons decreased, and NEUTRAL-neurons did not change their discharge rate prior to a limb withdrawal induced by noxious stimulation of the skin. Spontaneous activity and heat-evoked responses of ON-neurons were not different between neuropathic and control animals, whereas their mechanically evoked responses were reduced in neuropathy. Response properties of OFF-neurons were not different between neuropathic and control animals. Spontaneous activity of NEUTRAL-neurons was not different between neuropathic and control animals. (d-Tyr)L(Me-Phe)QPQRF-amide in the periaqueductal gray had no significant effect on evoked responses or spontaneous activity of ON- or OFF-neurons, independent of the experimental group. However, (d-Tyr)L(Me-Phe)QPQRF-amide produced a significant attenuation of spontaneous activity of NEUTRAL-neurons in neuropathic animals. In a behavioral study performed in unanesthetized animals it was found that intrathecal administration of methysergide, a serotonin antagonist, selectively attenuated neuropathic symptoms. Also, light pentobarbitone anesthesia markedly attenuated, but did not abolish, behaviorally determined neuropathic symptoms. From these results we suggest that NEUTRAL-neurons of the rostroventromedial medulla may have a role in neuropathy and they may be involved in attenuation of mechanical hypersensitivity by (d-Tyr)L(Me-Phe)QPQRF-amide in the periaqueductal gray. It is proposed that in neuropathy the synaptic effects of descending impulses from medullary NEUTRAL-neurons on their axonal targets in the spinal cord are changed so that this contributes to mechanical hypersensitivity, due to mechanisms that are at least partly serotoninergic.

Methysergide reduces nonnutritive blood flow in normal and scalded skin.

Methysergide is a serotonin antagonist and has been demonstrated to reduce wound blood flow and edema formation. We have determined the effect of methysergide on protein kinetics in normal and scalded skin of anesthetized rabbits. L-[ring-(13)C(6)]- or L-[ring-(2)H(5)]phenylalanine was used to reflect skin protein kinetics by use of an ear model, and L-[1-(13)C]leucine was used to reflect whole body protein kinetics. The results were that infusion of methysergide (2-3 mg. kg(-1). h(-1)) reduced the blood flow rate in normal skin by 50% without changing skin or whole body protein kinetics. After scald injury on the ear, administration of methysergide for 48 h reduced the weight of scalded ears (43 +/- 4 vs. 30 +/- 5 g, P < 0.01) and ear blood flow rate (42.6 +/- 4.9 vs. 5.8 +/- 1.0 ml. 100 g(-1). min(-1), P < 0.0001) and did not change wound protein kinetics. Methysergide reduced arteriovenous shunting and maintained inward phenylalanine transport from the blood to the skin pool. Using the microsphere technique, we found that the infusion of methysergide decreased blood perfusion by 33-36% in both normal and scalded ear skin. We conclude that methysergide administration reduces nonnutritive, as opposed to nutritive, blood flow in normal and scalded skin.

Anaphylactic bronchoconstriction in BP2 mice: interactions between serotonin and acetylcholine.

1. Immunized BP2 mice developed an acute bronchoconstriction in vivo and airway muscle contraction in vitro in response to ovalbumin (OA) and these contractions were dose dependent. 2. Methysergide or atropine inhibited OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro. 3. Neostigmine potentiated the OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro of BP2 mice. This potentiation was markedly reduced by the administration of methysergide or atropine and when the two antagonists were administered together, the responses were completely inhibited. 4. Neostigmine also potentiated the serotonin (5-HT)- and acetylcholine (ACh)-induced bronchoconstriction and this potentiation was significantly reversed by atropine. 5. These results indicate that OA provokes a bronchoconstriction in immunized BP2 mice by stimulating the release of 5-HT, which in turn acts via the cholinergic mediator, ACh.

Effects of Methysergide and Loratadine on Food Intake, Mood, and Performance of Humans Living in a Residential Laboratory

COMER, S. D., M. HANEY, A. S. WARD, M. W. FISCHMAN AND R. W. FOLTIN. Effects of methysergide and loratadine on food intake, mood, and performance of humans living in a residential laboratory. Physiol Behav 64(2) 159–164, 1998. The effects of loratadine, a peripherally acting histamine (H1) antagonist, and methysergide, a serotonin (5-HT) antagonist, were evaluated in seven normal-weight, male research volunteers, participating in a placebo-controlled, double-blind, 17-day residential study. Participants received oral loratadine (10 or 20 mg), methysergide (4 or 8 mg), or placebo at 1000 and 1700 hours daily. Active drug was administered on Days 4, 5, 7, 8, 11, 12, 15, and 16; placebo was administered on all other days. Drug and dose order were counterbalanced across participants. Food intake, performance, and subjective ratings were measured repeatedly throughout the day. Loratadine had no effect on food intake, performance, or subjective ratings. In contrast, total caloric intake significantly decreased from approximately 3500 kcal during placebo administration to 3065 kcal on the first but not the second day of methysergide administration. Consumption of carbohydrate ( p < 0.055), protein, and fat decreased on the first day of methysergide administration. This decrease in food intake was due to a decrease in meal size; the number of meals consumed was not affected. The proportion of calories derived from carbohydrates significantly increased on the first day of methysergide administration. Methysergide also significantly impaired performance of a psychomotor task on the first day of high-dose administration and increased ratings of several subjective measures, including “Vomiting,” “Stomach Pain,” and “Miserable.” These results suggest that the anorectic effect occurred as a result of the somatic and mood changes produced by methysergide. In addition, the inability of loratadine to affect food intake indicates that antagonism of central histamine receptors may be responsible for the increases in food intake produced by other antihistamines (e.g., diphenhydramine).

Involvement of Serotonin in the Modulation of Cocaine-Induced Locomotor Activity in the Rat

The influence of serotonin (5-HT) antagonists and a selective serotonin reuptake inhibitor (SSRI) on cocaine-induced locomotor activity, rears, and head bobs was investigated in female Glaxo Wistar rats. The SSRI, fluoxetine (10 mg/kg), and the nonselective 5-HT agent, methysergide, at the dose range of 5 and 15 mg/kg enhanced the behaviors produced by cocaine (15 mg/kg) to a similar extent. Moreover, the potentiation of cocaine-induced locomotor activity, rears, and head bobs was even greater after the combined administration of methysergide (15 mg/kg) and fluoxetine (10 mg/kg). In order to investigate a possible involvement of 5-HT 1A receptors in the observed potentiation by methysergide and fluoxetine, the potent and selective 5-HT 1A antagonist, WAY 100635, was used. WAY 100635 (0.1 and 1.5 mg/kg) markedly reduced the behaviors induced by cocaine preceded by fluoxetine (10 mg/kg) and methysergide (5 and 15 mg/kg) pretreatment, respectively, suggesting an involvement of 5-HT 1A receptors in the action of fluoxetine and methysergide on cocaine-induced behaviors. An attenuation of the fluoxetine-enhanced cocaine-induced behaviors was also observed after pretreatment with the 5-HT 2A antagonist ketanserin (0.1 and 1.0 mg/kg). Coadministration of ketanserin (1.0 mg/kg) and WAY 100635 (1.5 mg/kg) resulted in the greatest blockade of the fluoxetine-enhanced cocaine-induced behaviors. The antagonists and the SSRI, fluoxetine, did not alter the behaviors in comparison to that of saline-treated animals. These results provide evidence for an involvement of 5-HT 1A receptors in the enhancing effect of fluoxetine and methysergide on cocaine-induced locomotor activity, rears, and head bobs, and suggest a stimulatory action of methysergide at the 5-HT 1A receptor. In addition, some of the actions may also be mediated by activation of the 5-HT 2A receptor and/or inhibition of the 5-HT 2C receptor.

Involvement of serotonin in the regulation of GnRh gene expression in the male rat brain

The role of serotonin (5-HT) in the regulation of the hypothalamo-pituitary-gonadal axis is still controversial. In order to evaluate the influence of 5-HT on gonadotropin-releasing hormone (GnRH) neurons, we have investigated the effects of repeated administration (during 2 days) of 5-HT, the 5-HT1+2 receptor antagonist methysergide, the 5-HT2 receptor antagonist ketanserin, and the 5-HT3 receptor antagonist ondansetron on GnRH mRNA levels in the male rat medial preoptic area (MPOA), as measured by quantitative in situ hybridization. The treatment with 5-HT decreased by 32% the number of silver grains overlying labelled neurons. The administration of methysergide and ketanserin increased the hybridization signal by 32% and 29%, respectively. On the other hand, the 5-HT3 receptor antagonist did not modify GnRH mRNA levels. The present results clearly indicate that the serotoninergic system exerts a negative tonic influence on the biosynthesis of GnRH as evaluated by mRNA level measurements. They also strongly suggest that the influence of 5-HT in the regulation of GnRH neuronal activity is mediated via activation of 5-HT2 receptor, although an involvement of 5-HT1 receptors cannot be totally excluded.

Lateral habenula and hippocampal units: electrophysiological and iontophoretic study

In previous works we studied, on cats, the effects of lateral hobenula (LH) stimulation on hippocampal units. In particular, the results showed an excitation or an inhibition in relation to the stimulation frequency (0.5–3.0 Hz or 5.0–20 Hz, respectively). All the LH stimulation effects were antagonised by iontophoretic Intrahippocampal application of methysergide (MS). M this series of experiments It was possible to demonstrate, on rats, that LH stimulation causes an excitatory effect in a major number of hippocampal units in relation to the frequency increase. The inhibitory effect by iontophoretic serotonine application and the reversible blockade of habenular modulation after fontophoretic methysergide administration on hippocampal units suggest, on rats, the involvement of raphe. Such hypothesis, with anatomical evidences demonstrating an excitatory projection between LH and raphe, was confirmed by data concerning the effects of intraraphal NMDA iontophoretic application on hippocampal units (NMDA application for 30 s = excitation; NMDA administration for 10–15 min = inhibition). All the results suggest an habenular modulation of hippocampus through the Invohmment of the raphe in the context of which an interneurone Is Inhibitory on the efferent serotonergic raphe hippocampus pprojection. This hypothesis finds further support from MS blockade effect during Intreraphol NMDA iontophoretic administration.

Effects of methysergide administration on edema formation at the site of scald

Femoral blood flow (Qa), hind paw lymph flow (Qlym), and lymph-to-plasma protein concentration ratio (Clym/Cp) were monitored before and 4 h after 1) 5-s 100 degrees C paw scald, 2) methysergide (1 mg/kg iv) 20 min before scald, 3) methysergide 30 min after scald, and 4) methysergide only. Before experimentation, hind paw venous pressure was elevated and maintained until steady-state Qa, Qlym, and minimal Clym/Cp levels were reached. The reflection coefficient (sigma d) was determined as 1 - minimal Clym/Cp; the filtration coefficient (Kf) was calculated. Methysergide alone caused no changes. Increases in Qa, Qlym, Clym/Cp, and Kf were identified in all scald groups. Compared with scald only animals, pre- and postscald methysergide blunted the increases in Qa, Qlym, Kf, and paw weight gain without an effect on sigma d. These data demonstrate that methysergide reduces edema formation at the site of scald, perhaps by modulating the burn-induced vasodilator response and/or by limiting the burn-induced increase in microvascular surface area.

Effects of vagal afferent nerve stimulation on noxious heat-evoked Fos-like immunoreactivity in the rat lumbar spinal cord.

Electrophysiological and behavioral studies have described modulation of nociception by vagal afferent fibers. The objectives of this study were to 1) use Fos-like immunoreactivity as a marker for neuronal activity to examine populations of neurons in the spinal cord that are activated by a noxious heat stimulus, 2) determine whether heat-evoked Fos-like immunoreactivity can be modulated by vagal afferent stimulation, and 3) determine whether vagally-mediated effect on heat-evoked Fos-like immunoreactivity can be blocked by intrathecally administered serotoninergic receptor and alpha-adrenergic receptor antagonists. Neurons demonstrating Fos-like immunoreactivity were located in the ipsilateral superficial and deep dorsal horn laminae extending from the caudal L3 through the rostral L6 region of the spinal cord. Stimulation of the right cervical vagus nerve attenuated significantly (42%) heat-evoked Fos-like immunoreactivity in the superficial laminae. The reduction in Fos-like immunoreactivity by vagal stimulation was abolished by intrathecal administration of methysergide, a nonselective serotoninergic receptor antagonist, but not by phentolamine, a nonselective alpha-adrenoceptor antagonist. These results suggest that vagal afferent modulation of spinal nociceptive transmission is mediated, at least in part, by serotonin receptors.

Role of serotonin in the regulation of prolactin gene expression in the male rat as evaluated by in situ hybridization

It is well documented that serotonin (5-HT) is involved in the regulation of prolactin (PRL) release as a stimulator. To evaluate the role of 5-HT on PRL gene expression, we have investigated the effects of repeated administration (during 2 days) of 5-HT, the 5-HT 1+2 receptor antagonist methysergide, the 5-HT 2 receptor antagonist ketanserin, and a combination of 5-HT and methysergide on PRL mRNA levels as measured by in situ hybridization in the adult male rat. The treatment with 5-HT induced a 14% increase in the hybridization signal, although the administration of methysergide produced a small reduction (5%) in PRL mRNA levels. On the other hand, ketanserin had no effect on the hybridization signal. The stimulatory effect of 5-HT was completely prevented by the concomitant administration of methysergide. The present results, together with previous data, indicate that 5-HT exerts a positive tonic influence not only on the release of PRL but on the biosynthesis of the hormone as evaluated by mRNA level measurements. They also strongly suggest that the role of 5-HT in the regulation of PRL secretion is mediated via activation of 5-HT 1 receptors, although a dopaminergic effect of methysergide on PRL secretion cannot be totally excluded.

Increased neuropeptide Y concentrations in specific hypothalamic nuclei of the rat following treatment with methysergide: Evidence that NPY may mediate serotonin's effects on food intake

Neuropeptide Y (NPY) is a potent central appetite stimulant found in hypothalamic neurons that have close anatomical associations with neurons containing serotonin, a powerful anorectic agent. To determine whether the two neurotransmitters interact functionally, we have studied the effects on regional hypothalamic NPY concentrations of acute and chronic administration of methysergide, a 5-HT1 BC/ serotonin receptor antagonist. Chronic methysergide treatment (10 mg/kg/day) was given by subcutaneously implanted osmotic minipumps ( n = 8). Acute effects of methysergide were determined 4 h after a single injection (10 mg/kg) in a separate group ( n = 8). Controls ( n = 8) had implanted minipumps delivering saline, and also received a saline injection 4 h before sacrifice. Food intake was significantly increased ( p < 0.01) by both acute and chronic methysergide treatment. In the chronically treated rats, NPY levels were significantly increased over controls in the arcuate nucleus (ARC; by 41%, p = 0.02) and paraventricular nucleus (PVN; by 40%, p < 0.01). Acute methysergide treatment also increased NPY concentrations in the ARC (by 81%, p < 0.01) and PVN (by 30%, p < 0.01). Methysergide administration, which stimulated feeding, therefore raised NPY concentrations in the ARC, where NPY is synthesized, and in the PVN, a major site of NPY release where NPY injection induces hyperphagia. These findings suggest that NPYergic and serotoninergic innervations in the hypothalamus interact to regulate food intake, and raise the possibility that increased NPY release may mediate the hyperphagic effect of serotoninergic 5-HT1 BC/ receptor blockade.