The effect of serotonin on penicillin-induced epileptiform activity.

OBJECTIVE: This study was aimed at examining the epileptiform activity of the 5-HT2 serotonin receptor agonist and antagonist, and 5-hydroxytryptophan (5-HTP) in penicillin-induced epilepsy in albino Wistar rats. METHODS: For this purpose, 90 albino male Wistar rats were used in this study. Epileptiform activity was induced by an injection of penicillin, an agonist of GABAA receptor, (500 IU, i.c.) into the somatomotor cortex. Thirty minutes after the injection of penicillin, 2,5-dimethoxy-4-iodoamphetamine (DOI, an agonist of 5-HT2 receptor) (0.5, 1, 2 and 4 mg/kg, i.p.), methysergide, an antagonist of 5-HT2 receptor, (1, 10, 20, 50 and 100 µM, i.c.v.) and 5-HTP, precursor of 5-HT, (25, 50, 75 and 100 mg/kg, i.p.) were administered, respectively. RESULTS: DOI, at the doses of 1 and 2 mg/kg, significantly decreased penicillin-induced epileptiform activity (p < 0.05). Methysergide, at the doses of 20, 50 and 100 µM, significantly increased the mean spike frequency of penicillin-induced epileptiform activity (p < 0.05). The doses of 50, 75 and 100 mg/kg of 5-HTP decreased the mean spike frequency of penicillin-induced epileptiform activity (p < 0.05). The mean of amplitude of penicillin-induced epileptiform activity did not significantly change in any of the groups (p > 0.05). CONCLUSION: The electrophysiological data from the present study suggest that serotonin 5-HT2 receptors have an important role in controlling penicillin-induced epileptiform activity in the rat.

Intrathecal administration of clonidine or yohimbine decreases the nociceptive behavior caused by formalin injection in the marsh terrapin (Pelomedusa subrufa).

BACKGROUND: The role of noradrenergic system in the control of nociception is documented in some vertebrate animals. However, there are no data showing the role of this system on nociception in the marsh terrapins. METHODOLOGY: In this study, the antinociceptive action of intrathecal administration of the α 2-adrenoreceptor agonist clonidine and α 2-adrenoreceptor antagonist yohimbine was evaluated in the African marsh terrapin using the formalin test. The interaction of clonidine and yohimbine was also evaluated. RESULTS: Intrathecal administration of clonidine (37.5 or 65 µg/kg) caused a significant reduction in the mean time spent in pain-related behavior. Yohimbine, at a dose of 25 µg/kg, significantly blocked the effect of clonidine (65 µg/kg). However, administration of yohimbine (40 or 53 µg/kg) caused a significant reduction in the mean time spent in pain-related behavior. Intrathecal administration of yohimbine (53 µg/kg) followed immediately by intrathecal injection of the serotonergic methysergide maleate (20 µg/kg) resulted in a significant reversal of the antinociceptive effect of yohimbine. CONCLUSION: The present study documented the intrathecal administration of drugs in the marsh terrapin, a technique that can be applied in future studies on these animals. The data also suggest the involvement of both α 2-adrenoreceptors and 5HT receptors in the modulation of nociception in testudines.

[Therapy of trigeminal autonomic headaches]. / Therapie des trigeminoautonomen Kopfschmerzes.

Trigeminal autonomic cephalgias (TAC) are characterized by severe and strictly unilateral headaches with a frontotemporal and periorbital preponderance in combination with ipsilateral cranial autonomic symptoms, such as lacrimation, conjunctival injection, rhinorrhea, nasal congestion, and restlessness or agitation. One main differentiating factor is the duration of painful attacks. While attacks typically last 5 s to 10 min in SUNCT syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing), paroxysmal hemicrania lasts 2-30 min and cluster headaches 15-180 min. Hemicrania continua represents a continuous TAC variant. From a therapeutic view, TACs differ substantially. Lamotrigine is used as first-choice prevention in SUNCT syndrome and indometacin in paroxysmal hemicrania. For cluster headaches, acute therapy with inhaled pure oxygen and fast-acting triptans (sumatriptan s.c. and intranasal zolmitriptan) is equally important to short-term preventive therapy with methysergide and cortisone and long-term prophylactic treatment comprising verapamil as drug of first choice and lithium carbonate and topiramate as drugs of second choice. In refractory cases of chronic cluster headache, neuromodulatory approaches such as occipital nerve stimulation and sphenopalatine ganglion stimulation are increasingly applied.

Valvular heart disease associated with long-term treatment by methysergide: a case report.

This case report concerns a woman treated continuously since at least 10 years by methysergide for cluster headache. The echocardiographic and histological features of the severe valve fibrosis presented by this patient are very similar to those described with 5 HT(2B) receptors agonistic drugs.

Antinociceptive effect of stimulating the zona incerta with glutamate in rats.

The zona incerta (ZI) is a subthalamic nucleus connected to several structures, some of them known to be involved with antinociception. The ZI itself may be involved with both antinociception and nociception. The antinociceptive effects of stimulating the ZI with glutamate using the rat tail-flick test and a rat model of incision pain were examined. The effects of intraperitoneal antagonists of acetylcholine, noradrenaline, serotonin, dopamine, or opioids on glutamate-induced antinociception from the ZI in the tail-flick test were also evaluated. The injection of glutamate (7 µg/0.25 µl) into the ZI increased tail-flick latency and inhibited post-incision pain, but did not change the animal performance in a Rota-rod test. The injection of glutamate into sites near the ZI was non effective. The glutamate-induced antinociception from the ZI did not occur in animals with bilateral lesion of the dorsolateral funiculus, or in rats treated intraperitoneally with naloxone (1 and 2 m/kg), methysergide (1 and 2 m/kg) or phenoxybenzamine (2 m/kg), but remained unchanged in rats treated with atropine, mecamylamine, or haloperidol (all given at doses of 1 and 2 m/kg). We conclude that the antinociceptive effect evoked from the ZI is not due to a reduced motor performance, is likely to result from the activation of a pain-inhibitory mechanism that descends to the spinal cord via the dorsolateral funiculus, and involves at least opioid, serotonergic and α-adrenergic mechanisms. This profile resembles the reported effects of these antagonists on the antinociception caused by stimulating the periaqueductal gray or the pedunculopontine tegmental nucleus.

Role of TRPV1 in nociception and edema induced by monosodium urate crystals in rats.

Gout is characterized by the deposition of monosodium urate (MSU) crystals. Despite being one of the most painful forms of arthritis, gout and the mechanisms responsible for its acute attacks are poorly understood. In the present study, we found that MSU caused dose-related nociception (ED(50) [ie, the necessary dose of MSU to elicit 50% of the response relative to the control value]=0.04 [95% confidence interval 0.01-0.11]mg/paw) and edema (ED(50)=0.08 [95% confidence interval 0.04-0.16]mg/paw) when injected into the hind paw of rats. Treatment with the selective TRPV1 receptor (also known as capsaicin receptor and vanilloid receptor-1) antagonists SB366791 or AMG9810 largely prevented nociceptive and edematogenic responses to MSU. Moreover, the desensitization of capsaicin-sensitive afferent fibers as well as pretreatment with the tachykinin NK(1) receptor antagonist RP 67580 also significantly prevented MSU-induced nociception and edema. Once MSU was found to induce mast cell stimulation, we investigated the participation of these cells on MSU effects. Prior degranulation of mast cells by repeated treatment with the compound 48/80 decreased MSU-induced nociception and edema or histamine and serotonin levels in the injected tissue. Moreover, pretreatment with the mast cell membrane stabilizer cromolyn effectively prevented nociceptive and edematogenic responses to MSU. MSU induced a release of histamine, serotonin, and tryptase in the injected tissue, confirming mast cell degranulation. Furthermore, the antagonism of histaminergic H1 and serotoninergic receptors decreased the edema, but not the nociception of MSU. Finally, the prevention of the tryptase activity was capable of largely reducing both MSU-induced nociception and edema. Collectively, the present findings demonstrate that MSU produces nociceptive and edematogenic responses mediated by TRPV1 receptor activation and mast cell degranulation.

Subarachnoid serotonergic and noradrenergic antagonists increase the pain response in rats.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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%. RESULTS: In the intermediate phase the number of paw elevations was significantly higher in GF, GM, and GFM groups when compared to the GC group. CONCLUSIONS: 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.

Antagonistas serotoninérgico e noradrenérgico por via subaracnoidea aumentam a resposta álgica em ratos / Subarachnoid serotonergic and noradrenergic antagonists increase the pain response in rats

JUSTIFICATIVA E OBJETIVOS: Há evidências de que a passagem de informações nociceptivas pelo corno posterior da medula espinhal (CPME) seguindo para níveis rostrais do sistema nervoso central sofre profundas influências excitatórias e inibitórias. A presente pesquisa teve como objetivo comparar os efeitos da metissergida, da fentolamina e da fentolamina associada à metissergida, administrados por via subaracnoidea, sobre as fases I, intermediária e II do teste da formalina modificado em ratos. MÉTODO: Foram utilizados 28 ratos Wistar machos, distribuídos aleatoriamente em quatro grupos (n = 7) para receber solução salina (GC), fentolamina (GF), metissergida (GM) ou fentolamina associada à metissergida (GFM) por via subaracnoidea. A dor foi induzida pela administração de formalina na região dorsal da pata posterior direita. O teste foi dividido em três fases; fase I, intermediária e fase II. A análise estatística dos resultados foi realizada utilizando o programa SPSS (Statistical Package for Social Sciences), adotando o nível de significância de 5 por cento. RESULTADOS: Na fase intermediária, o número de elevações da pata foi significativamente maior nos grupos GF, GM e GFM quando comparados com o grupo GC. CONCLUSÕES: Os resultados sugerem a existência de efeito noradrenérgico e serotoninérgico no sistema inibitório descendente da dor aguda, com a possibilidade de emprego de agonistas serotoninérgicos e α1-adrenérgicos para controle da dor aguda.

BACKGROUND AND OBJECTIVES: 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 phormaline test in rats. METHODS: 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 phormaline 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 percent. RESULTS: In the intermediate phase the number of paw elevations was significantly higher in GF, GM, and GFM groups when compared to the GC group. CONCLUSIONS: 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.

JUSTIFICATIVA Y OBJETIVOS: Existen evidencias de que el paso de informaciones nociceptivas por el cuerno posterior de la médula espinal (CPME), y que continúa hacia niveles rostrales del sistema nervioso central, sufre profundas influencias excitatorias e inhibitorias. La presente investigación quiso comparar los efectos de la metisergida, de la fentolamina y de la fentolamina asociada a la metisergida, administrados por vía subaracnoidea, sobre las fases I, intermedia y II del test de la formalina modificado en ratones. MÉTODO: Fueron utilizados en el experimento, 28 ratones Wistar machos, distribuidos aleatoriamente en cuatro grupos (n = 7), para recibir una solución salina (GC), fentolamina (GF), metisergida (GM) o fentolamina asociada a la metisergida ((GFM). El dolor fue inducido por la administración de formalina en la región dorsal de la pata posterior derecha. El test fue dividido en tres fases: fase I, intermedia y fase II. El análisis estadístico de los resultados fue hecho utilizando el programa SPSS (Statistical Package for Social Sciences), [Paquete Estadístico para las Ciencias Sociales], adoptando el nivel de significancia de un 5 por ciento. RESULTADOS: En la fase intermedia, el número de elevaciones de la pata fue significativamente mayor en los grupos GF, GM y GFM cuando se comparó con el grupo GC. CONCLUSIONES: Los resultados nos sugieren la existencia de un efecto noradrenérgico y serotoninérgico en el sistema inhibitorio descendiente del dolor agudo, con la posibilidad del uso de agonistas serotoninérgicos y α1-adrenérgicos para el control del dolor agudo.

Discriminative stimulus effects of serotonin agonists, neutral antagonists, and inverse agonists in pigeons: perspectives on intrinsic efficacy measurements in vivo.

RATIONALE: The extended ternary complex theory of receptor function states a ligand can be classified as an inverse agonist, agonist, or neutral antagonist based on its ability to preferentially stabilize the inactive conformation, the active conformation, or to have no preference for conformational state, respectively. OBJECTIVES: While serotonin(2C) (5-HT(2C)) receptor ligands are classified accordingly in vitro, whether the phenomenon of inverse agonism manifests itself and/or is physiologically relevant in vivo is unknown. METHODS: Therefore, we tested a range of proposed agonists, neutral antagonists, and inverse agonists with activity at 5-HT(2C) receptors in three groups of pigeons trained to discriminate saline from: 1.0 mg/kg MK212, an agonist; 0.1 mg/kg methysergide, a proposed neutral antagonist; or, 10 mg/kg mianserin, a proposed inverse agonist. RESULTS: Based on the patterns of substitution, the discriminative stimulus effects of MK212 appear to be mediated through agonist actions and the stimulus effects of methysergide and mianserin appear to be mediated through antagonist actions. Selective 5-HT(2B/2C) inverse agonist SB206,553 (1 mg/kg) blocked the MK212 discriminative stimulus cue and substituted (0.32-10 mg/kg) in both methysergide- and mianserin-trained pigeons, confirming a 5-HT(2C) receptor role in mediating these discriminative stimuli. Inverse agonists and neutral antagonists fully substituted for methysergide. In addition to SB206,553, methysergide (0.032-1.0 mg/kg) and 5-HT(1A) agonist 8-OH-DPAT (0.32-1.0 mg/kg) substituted completely for mianserin suggesting a complex discriminative stimulus profile for this proposed inverse agonist. CONCLUSIONS: These data and the subsequent analyses suggest that the discriminative cues of MK212, methysergide, and mianserin are different and that the drug discrimination paradigm is a useful functional assay to examine intrinsic efficacy in vivo.

Forebrain regions affected by lateral parabrachial nucleus serotonergic mechanisms that influence sodium appetite.

Blockade of serotonergic receptors in the lateral parabrachial nucleus (LPBN), via bilateral injections of nonselective 5-hydroxytryptamine (5-HT)(1/2)-receptor antagonist, methysergide causes a robust sodium appetite. Our aim was to elucidate which brain regions are activated when serotonergic pathways to the LPBN are blocked and combined with subcutaneous injection of isoproterenol causing a salt appetite. In the experimental group, conscious rats were administered methysergide (4 microg/0.2 microl) injected bilaterally into the LPBN. Control groups included rats administered with injections of vehicle bilaterally into the LPBN, rats administered methysergide into injection sites outside the LPB region, and rats that did not undergo surgery. Each group was treated with a subcutaneous injection of isoproterenol (30 microg/kg), a beta-adrenergic agonist, and NaCl and water intakes were measured over 2h. Bilateral injections of methysergide into the LPBN followed by subcutaneous isoproterenol induced a strong intake of 0.3M NaCl (p<0.01) compared with all controls. Greater numbers of c-Fos-positive stained nuclei were observed in all brain regions assessed. The extended amygdala is rich in AT(1) receptors and ablation of these regions has been shown to reduce sodium appetite; therefore, neurons in these sites, and to a lesser extent the lamina terminalis, are likely primary targets of an inhibitory mechanism arising from the LPBN that acts to modulate sodium appetite.

Anticonvulsant serotonergic and deep brain stimulation in anterior thalamus.

OBJECTIVE: Anterior thalamus (AN) has been shown to mediate seizures in both focal and generalized models. Specific regional increase in AN serotonergic activity was observed following AN-DBS in our pentylenetetrazol (PTZ) rodent model of acute seizures, and this increase may inhibit seizures and contribute to the mechanism of anticonvulsant DBS. METHODS: Anesthetized rats with AN-directed dialysis cannula with scalp/depth EEG were infused with PTZ at 5.5mg/(kg min) until an EEG seizure occurred. Eight experimental groups of AN-dialysis infusion were evaluated: controls (dialysate-only), 10 and 100 microM serotonin 5-HT(7) agonist 5-carboxamidotryptamine (5-CT), 1, 10 and 100 microM serotonin antagonist methysergide (METH), AN-DBS, and 100 microM METH+AN-DBS. RESULTS: Latency for seizures in control animals was 3,120+/-770 s (S.D.); AN-DBS delayed onset to 5018+/-1100 (p<0.01). AN-directed 5-CT increased latency in dose-dependent fashion: 3890+/-430 and 4247+/-528 (p<0.05). Methysergide had an unexpected protective effect at low-dose (3908+/-550, p<0.05) but not at 100 microM (2687+/-1079). The anticonvulsant action of AN-DBS was blocked by prior dialysis using 100 microM METH. Surface EEG burst count and nonlinear analysis (H-Statistic) noted significant (p<0.05) increased pre-ictal epileptiform bursts in 5-CT, methysergide, but not DBS group compared to control. CONCLUSION: Increased serotonergic activity in AN raised PTZ seizure threshold, similar to DBS, but without preventing cortical bursting. 5-Carboxamidotryptamine, a 5-HT(7) agonist, demonstrated dose-dependent seizure inhibition. Methysergide proved to have an inverse, dose-dependent agonist property, antagonizing the action of AN-DBS at the highest dose. Anticonvulsant AN-DBS may in part act to selectively alter serotonin neurotransmission to raise seizure threshold.

Evaluation of serotonin as a feedback inhibitor of lactation in the bovine.

Serotonin (5-HT), a neurotransmitter synthesized from tryptophan, has been proposed as a feedback inhibitor of lactation. We determined that the gene coding for tryptophan hydroxylase 1, the rate-limiting enzyme for 5-HT synthesis, is expressed in bovine mammary epithelial cells in vitro and is upregulated by prolactin. In addition, 5-HT reduced the expression of alpha-lactalbu-min and casein genes in vitro. Furthermore, inhibiting 5-HT synthesis with p-chlorophenylalanine or blocking the 5-HT receptor with methysergide (METH) increased milk protein gene expression. We then evaluated effects of intramammary 5-HT or METH infusion on production and milk composition in 6 multiparous Holstein cows. Cows were assigned to a repeated measures design of contralateral intramammary infusions of METH (20 mg/quarter per d) or saline for 3 d followed by a 7-d washout period before administering 5-HT (50 mg/quarter/d) or SAL for 3 d. For each udder half, milk yield was recorded twice and composition was determined once per day. Blood samples were harvested each day for plasma to determine glucose and nonesterified fatty acid concentrations. Evaporative heat loss, respiration rate, left and right udder temperatures, and rectal temperatures were obtained after each milking to evaluate possible systemic effects of infusions. During METH and saline infusions milk yield increased 10.9%. During 5-HT and saline infusion milk yield decreased 11.1%. Milk yield and physiological responses suggested intramammary 5-HT and METH doses were high enough to cause systemic effects. Infusing saline, METH, and 5-HT increased milk SCC. Infusing 5-HT tended to reduce mean lactose concentration (4.3 vs. 4.6%) relative to saline. Milk protein content was decreased by METH and SAL (2.0%) and was increased (5.8%) by 5-HT followed by a 33% decrease postinfusion. Infusion of METH increased evaporative heat loss 11%, which decreased 11% postinfusion. Infusions of 5-HT or METH did not affect plasma nonesterified fatty acid or glucose concentrations, respiration rate, or milk fat content. We conclude 5-HT infusion reduced milk synthesis, whereas blocking the 5-HT receptor with METH increased milk synthesis. Doses of 5-HT and METH used in this study likely resulted in systemic effects. These data support the concept that 5-HT is a feedback inhibitor of lactation in the bovine.

Behavioral effects of the beta3 adrenoceptor agonist SR58611A: is it the putative prototype of a new class of antidepressant/anxiolytic drugs?

A large body of evidence corroborates the notion that deficiencies of serotonergic system are likely involved in the pathogenesis of both depression and anxiety. Activation of beta(3) adrenoceptors has been shown to increase brain tryptophan content suggesting an elevation of brain serotonin (5HT) synthesis. SR58611A is a selective beta(3) adrenergic agent possessing a profile of antidepressant activity in routine rodents' experimental models of depression. The present study was undertaken to evaluate in rodents the antidepressant properties of SR58611A and to assess its putative anxiolytic value in experimental models of depression and anxiety. Compared to the control group, SR58611A (0.1, 1, 5 or 10 mg/kg) caused a dose-dependent reduction in immobility of Wistar male rats in the forced swim test. The maximum dose appeared to be equivalent to an effective dose of clomipramine (50 mg/kg). In addition, acute injection of SR58611A induced in rats a dose-dependent decrease in grooming response to a novel environment (novelty-induced grooming test). For any dose, the effect was lower than that of diazepam (1 mg/kg). Chronic treatment with SR58611A resulted also in an increased social interaction time in the social interaction test without affecting motor activity of rats. Furthermore, similarly to diazepam a chronic treatment with the highest doses of SR58611A was followed by increased exploratory behavior in Swiss male mice exposed to the elevated plus maze test. These effects are mediated by beta(3) adrenoceptors since i.p. pretreatment with the selective beta(3) adrenoceptor antagonist SR59230A (5 mg/kg) blocked the effects of SR58611A. Finally, also the 5HT antagonist methysergide (2 mg/kg) prevented the antidepressant and anxiolytic-like activity of SR58611A indicating that 5HT transmission is strictly involved in its action.

Intake of fermented soybean (natto) increased locomotor activity in mice.

We fed mice food granules containing fermented soybean (natto in Japanese) powder (hereafter "natto granules") for 14 d to investigate whether natto granules had any effects on mouse behavior. We noted an enhancement of locomotor activity in natto-granule-fed mice compared to control and soybean-pellet-fed mice. This enhanced locomotor activity was blocked by a low dose of haloperidol (1 microg/kg i.p.), a dopamine receptor antagonist, but not by methysergide, a serotonin 5-HT(1/2) receptor antagonist. The results suggest that the enhanced locomotor activity induced by continuous intake of natto granules in mice is sensitive to haloperidol.

Serotonergic mechanisms of the lateral parabrachial nucleus in renal and hormonal responses to isotonic blood volume expansion.

This study investigated the involvement of serotonergic mechanisms of the lateral parabrachial nucleus (LPBN) in the control of sodium (Na+) excretion, potassium (K+) excretion, and urinary volume in unanesthetized rats subjected to acute isotonic blood volume expansion (0.15 M NaCl, 2 ml/100 g of body wt over 1 min) or control rats. Plasma oxytocin (OT), vasopressin (VP), and atrial natriuretic peptide (ANP) levels were also determined in the same protocol. Male Wistar rats with stainless steel cannulas implanted bilaterally into the LPBN were used. In rats treated with vehicle in the LPBN, blood volume expansion increased urinary volume, Na+ and K+ excretion, and also plasma ANP and OT. Bilateral injections of serotonergic receptor antagonist methysergide (1 or 4 microg/200 etal) into the LPBN reduced the effects of blood volume expansion on increased Na+ and K+ excretion and urinary volume, while LPBN injections of serotonergic 5-HT(2a)/HT(2c) receptor agonist, 2.5-dimetoxi-4-iodoamphetamine hydrobromide (DOI; 1 or 5 microg/200 etal) enhanced the effects of blood volume expansion on Na+ and K+ excretion and urinary volume. Methysergide (4 microg) into the LPBN decreased the effects of blood volume expansion on plasma ANP and OT, while DOI (5 microg) increased them. The present results suggest the involvement of LPBN serotonergic mechanisms in the regulation of urinary sodium, potassium and water excretion, and hormonal responses to acute isotonic blood volume expansion.

Involvement of skin barrier dysfunction in itch-related scratching in special diet-fed hairless mice.

HR-1 hairless mice fed with a special diet develop atopic-like dry skin, characterized by increased transepidermal water loss, and prolonged bouts of spontaneous scratching. In this study, the role of the skin barrier dysfunction in the prolongation of scratching was evaluated. Although the prolonged scratching was dose-dependently inhibited by opioid receptor antagonist naloxone, neither H(1) receptor antagonist, mepyramine, nor 5-HT(1/2) receptor antagonist, methysergide, affected it. Thus, the prolonged scratching could be itch-related response independent of histamine and serotonin. The application of petrolatum ointment on the skin temporarily alleviated the increase of transepidermal water loss for 60 min after treatment. Due to this alleviation in barrier dysfunction, the prolongation of scratching was significantly suppressed. However, when the barrier dysfunction relapsed, the scratching worsened. Taken together, a skin barrier dysfunction is associated with the itch-related response.

Ethanol substitutes for the discriminative stimulus effects of m-chlorophenylpiperazine.

Rats were trained to discriminate the 5-HT agonist m-chlorophenylpiperazine (mCPP, 1 mg/kg, i.p.) from saline. Ethanol (0.1 to 1 g/kg, i.p.) partially substituted for the discriminative stimulus effects of 1 mg/kg mCPP. Methysergide (10 mg/kg, i.p.), a 5-HT(1/2) receptor antagonist, blocked the ability of ethanol (1 g/kg) to substitute for mCPP. The largest dose of ethanol markedly reduced response rate. These findings suggest an important role of serotonin receptors in mediating the discriminative stimulus effects of ethanol.

[Current views on migraine and anti-migraine preparations]. / Sovremennye predstavleniia o migreni i mekhanizmakh deistviia sredstv dlia ee lecheniia i profilaktiki.

On the basis of comprehensive experimental and clinical research the authors defined a variety of migraine-related mechanisms and schemes of migraine-correction by drugs, which should be both of the vascular- and general-actions to ensure an effective medication.

Spinal 5-HT(2) and 5-HT(3) receptors mediate low, but not high, frequency TENS-induced antihyperalgesia in rats.

Transcutaneous electrical nerve stimulation (TENS) is a form of non-pharmacological treatment for pain. Involvement of descending inhibitory systems is implicated in TENS-induced analgesia. In the present study, the roles of spinal 5-HT and alpha(2)-adrenoceptors in TENS analgesia were investigated in rats. Hyperalgesia was induced by inflaming the knee joint with 3% kaolin-carrageenan mixture and assessed by measuring paw withdrawal latency (PWL) to heat before and 4 h after injection. The (1). alpha(2)-adrenergic antagonist yohimbine (30 microg), (2). 5-HT antagonist methysergide (5-HT(1). and 5-HT(2). 30 microg), one of the 5-HT receptor subtype antagonists, (3). NAN-190 (5-HT(1A), 15 microg), (4). ketanserin (5-HT(2A), 30 microg), (5). MDL-72222 (5-HT(3), 12 microg), or (6). vehicle was administered intrathecally prior to TENS treatment. Low (4 Hz) or high (100 Hz) frequency TENS at sensory intensity was then applied to the inflamed knee for 20 min and PWL was determined. Selectivity of the antagonists used was confirmed using respective agonists administered intrathecally. Yohimbine had no effect on the antihyperalgesia produced by low or high frequency TENS. Methysergide and MDL-72222 prevented the antihyperalgesia produced by low, but not high, frequency TENS. Ketanserin attenuated the antihyperalgesic effects of low frequency TENS whereas NAN-190 had no effect. The results from the present study show that spinal 5-HT receptors mediate low, but not high, frequency TENS-induced antihyperalgesia through activation of 5-HT(2A) and 5-HT(3) receptors in rats. Furthermore, spinal noradrenergic receptors are not involved in either low or high frequency TENS antihyperalgesia.