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Menopause status has been associated with an increase in venous diseases and lower limb-related symptoms. The purpose of our study was to evaluate pain associated with chronic venous insufficiency and its risk factors in postmenopausal women.A controlled cross-sectional study was performed in 139 postmenopausal women with chronic venous insufficiency and 40 control women. Pain was assessed with a visual analogue scale, the McGill Pain Questionnaire, and the Pain Matcher (Cefar Medical AB, Lund, Sweden). The influence of several demographic and clinical risk factors was analyzed using bivariate and multivariate regression analyses.Women in the chronic venous insufficiency group had significantly higher pain intensity and significantly lower pain threshold (P = 0.001) than the control group. The level of pain was independently and significantly associated with venous refill time and osteoarthritis index scores. It was not associated with other risk factors or with disease severity according to the clinical, etiological, anatomical, and pathophysiological classification.Venous pain is a consistent symptom in postmenopausal women with chronic venous insufficiency, in whom nociceptive thresholds are generally decreased. Reduced physical activity, venous reflux, and osteoarthritis seem to influence pain level in chronic venous insufficiency.

There is ample evidence of the biological changes produced by the sustained activation of opioid receptors. We evaluated the adaptive changes of cerebral Na + ,K + -ATPase in response to the sustained administration of morphine (minipumps, 45 mg/kg/day, 6 days) in CD-1 mice and the functional role of these changes in opioid antinociception. The antinociceptive effect of morphine as determined with tail-flick tests was reduced in morphine-tolerant mice. There were no significant changes in the density of high-affinity Na + ,K + -ATPase α subunits labeled with [ 3 H]ouabain in forebrain membranes from morphine-tolerant compared to those of morphine-naive animals. Western blot analysis showed that there were no significant differences between groups in the changes in relative abundance of α 1 and α 3 subunits of Na + ,K + -ATPase in the spinal cord or forebrain. However, the morphine-induced stimulation of Na + ,K + -ATPase activity was significantly lower in brain synaptosomes from morphine-tolerant mice (EC 50 = 1.79 ± 0.10 μM) than in synaptosomes from morphine-naive mice (EC 50 = 0.69 ± 0.12 μM). Furthermore, adaptive alterations in the time-course of basal Na + ,K + -ATPase activity were observed after sustained morphine treatment, with a change from a bi-exponential decay model (morphine-naive mice) to a mono-exponential model (morphine-tolerant mice). In behavioral studies the antinociceptive effects of morphine (s.c.) in the tail-flick test were dose-dependently antagonized by ouabain (1 and 10 ng/mouse, i.c.v.) in morphine-naive mice, but not in morphine-tolerant mice. These findings suggest that during morphine tolerance, adaptive cellular changes take place in cerebral Na + ,K + -ATPase activity which are of functional relevance for morphine-induced antinociception.

We evaluated the effect of haloperidol (HP) and its metabolites on [3H](+)-pentazocine binding to σ1 receptors in SH-SY5Y human neuroblastoma cells and guinea pig brain P1, P2 and P3 subcellular fractions. Three days after a single i.p. injection in guinea pigs of HP (but not of other σ1 antagonists or (−)-sulpiride), [3H](+)-pentazocine binding to brain membranes was markedly decreased. Recovery of σ1 receptor density to steady state after HP-induced inactivation required more than 30 days. HP-metabolite II (reduced HP, 4-(4-chlorophenyl)-α-(4-fluorophenyl)-4-hydroxy-1-piperidinebutanol), but not HP-metabolite I (4-(4-chlorophenyl)-4-hydroxypiperidine), irreversibly blocked σ1 receptors in guinea pig brain homogenate and P2 fraction in vitro. We found similar results in SH-SY5Y cells, which suggests that this process may also take place in humans. HP irreversibly inactivated σ1 receptors when it was incubated with brain homogenate and SH-SY5Y cells, but not when incubated with P2 fraction membranes, which suggests that HP is metabolized to inactivate σ1 receptors. Menadione, an inhibitor of the ketone reductase activity that leads to the production of HP-metabolite II, completely prevented HP-induced inactivation of σ1 receptors in brain homogenates. These results suggest that HP may irreversibly inactivate σ1 receptors in guinea pig and human cells, probably after metabolism to reduced HP.

The activation of specific subtypes of serine/threonine protein phosphatases (PPs) plays a role in the antinociceptive effect of acute morphine, but it is not known whether these enzymes are involved in morphine-induced antinociception in morphine-tolerant animals. We evaluated the effects of both okadaic acid (a selective inhibitor of some serine/threonine PPs) and its inactive analogue L-norokadaone on the antinociception induced by morphine in morphine-naive and -tolerant female mice in the tail-flick test. Okadaic acid (0.01 and 1 pg/mouse, i.c.v.), but not L-norokadaone (1 pg/mouse, i.c.v.), antagonized in a dose-dependent way the antinociception induced by morphine (1–16 mg/kg, s.c.) in morphine-naive animals. However, both okadaic acid (0.01 and 1 pg/mouse, i.c.v.) and L-norokadaone (1 pg/mouse, i.c.v.) were unable to modify the antinociceptive effect of morphine in morphine-tolerant mice. These results suggest that in morphine-induced thermal analgesia, the role of serine/threonine PPs highly sensitive to okadaic acid is different in morphine-tolerant and morphine-naive female mice.

Hospital mortality related to adverse drug reactions (ADRs) is a relevant clinical problem with major health and economic consequences. We conducted a study to assess hospital mortality related to ADRs, the drugs most frequently involved, and the possible risk factors associated with fatal ADRs. A retrospective observational study was conducted, reviewing the clinical records of 1388 consecutive adult patients (18–101 years) who died during a 22-month period in a tertiary hospital in Southern Europe (Granada, Spain). The main outcome was the prevalence of hospital death suspected to be related to administered drugs. Out of the 1388 adult deaths studied, 256 (18.4 %) were suspected of being related to drugs. Drugs were suspected of causing death in 146 inpatients (10.5 %) and contributing to death in 110 (7.9 %). Drugs related to death were administered during the hospital stay in 161 cases (11.5 %) and before hospital admission in 95 (6.84 %). The most frequent fatal ADRs were cardiac arrhythmia, gastrointestinal bleeding, and respiratory failure. The drugs most frequently involved in fatal ADRs were antithrombotics (anticoagulants or antiplatelets) (23 %), psychotropic drugs (21.2 %), and digoxin (11.3 %). Independent risk factors for ADR-related death were the presence of ≥4 diseases (OR = 1.43) and the receipt of ≥10 drugs (OR = 3.24), but no significant association with gender or age was found. A high percentage of hospital deaths were suspected of being associated with ADRs, especially in patients with comorbidity and/or polypharmacy. Antithrombotics, psychotropics, and digoxin were the drugs most frequently associated with in-hospital drug-related deaths.

We previously reported that serine/threonine protein phosphatases (PPs) play a role in the antinociception induced by the mu-opioid receptor agonist morphine. In this study we evaluated the possible involvement of PPs on the antinociception induced by agonists of others G protein-coupled receptors in the tail flick test in mice. The subcutaneous administration of clonidine (0.25-4 mg/kg), baclofen (2-32 mg/kg) or U50,488H (2-16 mg/kg) (agonists of alpha(2) adrenoceptors, GABA(B) and kappa-opioid receptors, respectively) produced dose-dependent antinociception. The antinociceptive effects of clonidine and baclofen were antagonized in a dose-dependent way by the protein phosphatase inhibitors okadaic acid (0.001-10 pg/mouse, i.c.v.) and cantharidin (0.001-10 ng/mouse, i.c.v.), and okadaic acid was 1000 times more potent than cantharidin in producing this effect. The effects of these drugs appear to be specifically due to the blockade of PPs, since L-norokadaone (an analogue of okadaic acid that has no effect on PPs) did not modify clonidine- or baclofen-induced antinociception over the wide range of doses used (0.001-1000 pg/mouse, i.c.v.). On the other hand, the antinociception induced by activation of kappa-opioid receptors with U50,488H was not modified by okadaic acid or cantharidin. In conclusion, our data support the idea that serine/threonine PPs are differentially involved in the antinociceptive effects of several agonists of G protein-coupled receptors in mice.

We evaluated the modulation by Na+,K+-ATPase inhibitors of morphine-induced antinociception in the tail-flick test and [3H]naloxone binding to forebrain membranes. The antinociception induced by morphine (1-32 mg/kg, s.c.) in mice was dose-dependently antagonized by ouabain (1-10 ng/mouse, i.c.v.), which produced a significant shift to the right of the morphine dose-response curve. The i.c.v. administration of three Na+,K+-ATPase inhibitors (ouabain at 0.1-100, digoxin at 1-1,000, and digitoxin at 10-10,000 ng/mouse) dose-dependently antagonized the antinociceptive effect of morphine (4 mg/kg, s.c.) in mice, with the following order of potency: ouabain > digoxin > digitoxin. This effect cannot be explained by any interaction at opioid receptors, since none of these Na+,K+-ATPase inhibitors displaced [3H]naloxone from its binding sites, whereas naloxone did so in a concentration-dependent manner. The antinociception induced by morphine (5 mg/kg, s.c.) in rats was antagonized by the i.c.v. administration of ouabain at 10 ng/rat, whereas it was not significantly modified by intrathecally administered ouabain (10 and 100 ng/rat). These results suggest that the activation of Na+,K+-ATPase plays a role in the supraspinal, but not spinal, antinociceptive effect of morphine.

1. We evaluated the effects of the i.c.v. administration of different K+ channel blockers (gliquidone, 4-aminopyridine and tetraethylammonium) and an opener of K+ channels (cromakalim) on the antinociception induced by several mu-opioid receptor agonists in a tail flick test in mice. 2. The s.c. administration of all agonists of mu-opioid receptors tested (morphine, 1-16 mg kg-1; metadone, 1-6 mg kg-1; buprenorphine, 0.04-0.64 mg kg-1; fentanyl, 0.02-0.32 mg kg-1 and levorphanol, 0.2-3.2 mg kg-1) elicited a dose-dependent antinociceptive effect. 3. The ATP-sensitive K+ channel blocker, gliquidone (0.06-16 micrograms per mouse, i.c.v.) antagonized the antinociception induced by buprenorphine, morphine and metadone. In contrast, gliquidone (0.25-160 micrograms per mouse) did not modify the antinociceptive effects of fentanyl and levorphanol. 4. Cromakalim (4-64 micrograms per mouse, i.c.v.), an opener of ATP-sensitive K+ channels, enhanced the antinociception produced by buprenorphine, morphine, and methadone, and did not significantly modify the antinociceptive effects of fentanyl and levorphanol. 5. The i.c.v. administration of the K+ channel blockers tetraethylammonium (10 micrograms per mouse) or 4-aminopyridine (25 ng per mouse) did not significantly modify the antinociception induced by any mu-opioid receptor agonist tested. 6. These results suggest that the opening of ATP-sensitive K+ channels is involved in the antinociceptive effect of morphine, buprenorphine and methadone, but not in that of fentanyl or levorphanol. Consequently, we suggest that at least two subgroups can be distinguished among mu-opioid receptor agonists, each inducing antinociception through different effector mechanisms.

Several lines of evidence suggest that σ(1) receptors regulate intracellular calcium concentration [Ca(2+)](i). However, no previous studies have demonstrated a consistent role for these receptors in the modulation of extracellular calcium entry through plasmalemmal voltage-dependent calcium channels (VDCCs). To search for evidence of such a role we compared [Ca(2+)](i) under basal conditions and after depolarization with KCl in fura-2-loaded synaptosomes from wild-type and σ(1) receptor knockout (σ(1)R-KO) mice. We also tested the effects of the selective σ(1) receptor agonists PRE-084 and (+)-pentazocine and antagonists BD-1047 and NE-100 on the increase in [Ca(2+)](i) induced by depolarization with 60mM KCl. Mibefradil, a nonselective blocker of VDCCs, was used as a positive control. Basal [Ca(2+)](i) and the increase in [Ca(2+)](i) caused by KCl-induced depolarization were similar in brain synaptosomes from both wild-type and σ(1)R-KO mice. Mibefradil (1-30 μM) and all σ(1) receptor ligands studied (3-100 μM) inhibited the KCl-induced increase in [Ca(2+)](i) in a concentration-dependent way. The order of maximum inhibition for the ligands compared here was NE-100>BD-1047=PRE 084>(+)-pentazocine. There were no appreciable differences in their effects between wild-type and σ(1)R-KO mice. These findings indicate that σ(1) receptors are not involved in calcium influx through VDCCs or in the inhibitory effects of these σ(1) ligands on Ca(2+) channels.

Pharmacological treatment is the first that should be taken into account in dealing with neuropathic pain, antiepileptic drugs being one of the leading options. Levetiracetam is a state of the art antiepileptic drug that has displayed antinociceptive activity in experimental models of pain and clinical effectiveness as an analgesic in series of patients with neuropathic pain.To analyse the effectiveness of levetiracetam as an analgesic in the treatment of neuropathic pain by means of a systematic review of the literature.The Medline/PubMed database was used in the study and the search criteria included three fundamental elements: levetiracetam, neuropathic pain and patients. The studies identified were those published before 31st January 2011. The selected studies were submitted to a quality analysis according to the Physiotherapy Evidence Database scale (0-10).Three series of cases, two open non-controlled pilot studies and four randomised clinical trials (RCT) were selected. Only the RCT met acceptable quality criteria. The aetiology of the neuropathic pain was different in each of the RCT analysed. Levetiracetam proved to be effective in the treatment of neuropathic pain in the studies with a low level of methodological quality (case series and pilot studies) and in one RCT aimed at patients with central neuropathic pain due to multiple sclerosis.Few clinical trials with a high level of methodological quality have been conducted to evaluate the effectiveness of levetiracetam in the treatment of neuropathic pain and most of those that have been carried out do not show any benefit in comparison to the use of a placebo.

We evaluated the role of sigma(1) receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and sigma(1) receptor knockout (sigma(1)-KO) mice and selective sigma(1) receptor-acting drugs. Mutation in sigma(1)-KO mice was confirmed by PCR analysis of genomic DNA and, at the protein level, by [(3)H](+)-pentazocine binding assays. Both wild-type and sigma(1)-KO mice not treated with capsaicin showed similar responses to different intensities of mechanical stimuli (0.05-8 g force), ranging from innocuous to noxious, applied to the hind paw. This indicates that sigma(1) gene inactivation does not modify the perception of punctate mechanical stimuli. The intraplantar (i.pl.) administration of capsaicin induced dose-dependent mechanical allodynia in wild-type mice (markedly reducing both the threshold force necessary to induce paw withdrawal and the latency to paw withdrawal induced by a given force). In contrast, capsaicin was completely unable to induce mechanical hypersensitivity in sigma(1)-KO mice. The high-affinity and selective sigma(1) antagonists BD-1063, BD-1047 and NE-100, administered subcutaneously (s.c.), dose-dependently inhibited mechanical allodynia induced by capsaicin (1 microg,i.pl.), yielding ED(50) (mg/kg) values of 15.80+/-0.93, 29.31+/-1.65 and 40.74+/-7.20, respectively. The effects of the sigma(1) antagonists were reversed by the sigma(1) agonist PRE-084 (32 mg/kg, s.c.). None of the drugs tested modified the responses induced by a painful mechanical punctate stimulus (4 g force) in nonsensitized animals. These results suggest that sigma(1) receptors are essential for capsaicin-induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.

We evaluated the effect of haloperidol (HP) and its metabolites on [(3)H](+)-pentazocine binding to sigma(1) receptors in SH-SY5Y human neuroblastoma cells and guinea pig brain P(1), P(2) and P(3) subcellular fractions. Three days after a single i.p. injection in guinea pigs of HP (but not of other sigma(1) antagonists or (-)-sulpiride), [(3)H](+)-pentazocine binding to brain membranes was markedly decreased. Recovery of sigma(1) receptor density to steady state after HP-induced inactivation required more than 30 days. HP-metabolite II (reduced HP, 4-(4-chlorophenyl)-alpha-(4-fluorophenyl)-4-hydroxy-1-piperidinebutanol), but not HP-metabolite I (4-(4-chlorophenyl)-4-hydroxypiperidine), irreversibly blocked sigma(1) receptors in guinea pig brain homogenate and P(2) fraction in vitro. We found similar results in SH-SY5Y cells, which suggests that this process may also take place in humans. HP irreversibly inactivated sigma(1) receptors when it was incubated with brain homogenate and SH-SY5Y cells, but not when incubated with P(2) fraction membranes, which suggests that HP is metabolized to inactivate sigma(1) receptors. Menadione, an inhibitor of the ketone reductase activity that leads to the production of HP-metabolite II, completely prevented HP-induced inactivation of sigma(1) receptors in brain homogenates. These results suggest that HP may irreversibly inactivate sigma(1) receptors in guinea pig and human cells, probably after metabolism to reduced HP.

The present study evaluated the effects of phenytoin (DPH) on the binding to synaptosomal fraction membranes from guinea pig brain of the prototypic sigma1 (sigma1) receptor agonist [3H](+)-pentazocine and the putative sigma1 antagonist [3H]NE-100. Equilibrium and binding kinetics studies were done. The order of affinity of 12 sigma1 ligands for binding sites labeled with [3H](+)-pentazocine correlated well with their order of affinity for sites labeled with [3H]NE-100, suggesting that both radioligands label the same receptor. Phenytoin increased the binding of [3H](+)-pentazocine, enhancing its affinity (K(D) value) for sigma1 receptors and decreasing its dissociation rate from these receptors. The maximal number of receptors (B(max) value) labeled with [3H](+)-pentazocine was not changed. In contrast, phenytoin decreased the specific binding and maximal number of receptors labeled with [3H]NE-100, and increased its dissociation rate from sigma1 receptors. The affinity of this radioligand for sigma1 receptors was not modified. In conclusion, phenytoin behaved as a positive allosteric modulator on the binding of [3H](+)-pentazocine, whereas it negatively modulated the binding of [3H]NE-100. These results add evidence in favor of the use of phenytoin in vitro to distinguish between agonists and antagonists of sigma1 receptors.

We evaluated the effects of phenytoin (DPH) on the affinity for sigma-1 (sigma(1)) receptors of agonist or antagonist sigma(1) ligands in guinea pig brain. Heterologous competition experiments showed that DPH (250 microM and 1 mM) concentration-dependently increased the affinity of the sigma(1) agonists dextromethorphan, (+)-SKF-10,047, (+)-3-PPP, and PRE-084. However, neither DPH 250 microM nor 1 mM increased (in fact, they slightly decreased) the affinity of the sigma(1) receptor antagonists haloperidol, BD 1063, NE-100, progesterone, and BD 1047. These findings suggest that allosteric modulation by DPH of the affinity of sigma(1) receptor ligands depends on the agonist or antagonist characteristics of the ligand. Therefore, determining in vitro the differential modulation by DPH of sigma(1) ligand affinity appears to constitute a procedure that can predict the pharmacological profile of different sigma(1) ligands.

The aim of this study was to evaluate the effects of serine/threonine protein phosphatase (PP) inhibitors on morphine-induced antinociception in the tail flick test in mice, and on [3H]naloxone binding to the forebrain crude synaptosome fraction. Neither okadaic acid nor cantharidin (1-10000 nM) displaced [3H]naloxone from its specific binding sites, which indicates that they do not interact at the opioid receptor level. The i.c.v. administration of very low doses of okadaic acid (0.001-1 pg/mouse) and cantharidin (0.001-1 ng/mouse), which inhibit PP2A, produced a dose-dependent antagonism of the antinociception induced by morphine (s.c.). However, L-nor-okadaone (0.001 pg/mouse-1 ng/mouse, i.c.v.), an analogue of okadaic acid lacking activity against protein phosphatases, did not affect the antinociceptive effect of morphine. On the other hand, high doses of okadaic acid (10 ng/mouse, i.c.v.) and cantharidin (1 microg/mouse, i.c.v.), which also block PP1, and calyculin-A (0.1 fg/mouse-1 ng/mouse, i.c.v.), which inhibits equally both PP1 and PP2A, did not modify the morphine-induced antinociception. These results suggest that the activation of type 2A serine/threonine protein phosphatases may play a role in the antinociceptive effect of morphine, and that PP1 might counterbalace this activity.

Introduccion. El tratamiento farmacologico es la primera opcion que se debe considerar en el tratamiento del dolor neuropatico, en el que los antiepilepticos ocupan un lugar destacado. El levetiracetam es un antiepileptico de ultima generacion que ha mostrado actividad antinociceptiva en modelos experimentales de dolor y eficacia clinica analgesica en series de pacientes con dolor neuropatico. Objetivo. Analizar la eficacia analgesica del levetiracetam en el tratamiento del dolor neuropatico mediante una revision sistematica de la bibliografia. Pacientes y metodos. Se ha utilizado la base de datos Medline/PubMed. Los criterios de busqueda reunieron tres elementos fundamentales: levetiracetam, dolor neuropatico y pacientes. Se han identificado los estudios hasta el 31 de enero de 2011. Los estudios seleccionados se sometieron a un analisis de calidad segun la escala Physiotherapy Evidence Database (0-10). Resultados. Se seleccionaron tres series de casos, dos estudios pilotos abiertos y no controlados y cuatro ensayos clinicos aleatorizados (ECA). Solo los ECA reunieron criterios de calidad aceptables. La etiologia del dolor neuropatico era diferente en los distintos ECA analizados. El levetiracetam mostro eficacia en el tratamiento del dolor neuropatico en los estudios con calidad metodologica baja (series de casos y estudios pilotos) y en un ECA dirigido a pacientes con dolor neuropatico central debido a esclerosis multiple. Conclusiones. Hay escasos ensayos clinicos de calidad metodologica alta que evaluen la eficacia del levetiracetam en el tratamiento del dolor neuropatico y la mayoria de ellos no demuestra beneficio en relacion con el placebo.

The effect of gliquidone, an ATP-dependent K+ (KATP) channel blocker, on morphine-induced hypermotility in mice was studied. Morphine (5-40 mg/kg s.c.) dose dependently increased ambulatory activity. Gliquidone (10 micrograms/mouse i.c.v.) induced a parallel displacement to the right of the morphine dose-response curve. Moreover, gliquidone (10 and 40 micrograms/mouse i.c.v.) produced a dose-dependent antagonism of morphine (20 mg/kg s.c.)-induced hypermotility. These results suggest that KATP channels are involved in morphine-induced hypermotility. The present data, together with those of previous studies showing antagonism by KATP channel blockers of morphine-induced antinociception and hyperthermia, further indicate that the opening of KATP channels plays an important role in the mechanism of action of morphine.

The effects of four ATP-dependent K+ channel blockers (hypoglycemic sulfonylureas) against morphine- and U50488H-induced antinociception were evaluated using the tail flick test in mice. None of the sulfonylureas tested significantly modified tail flick latency in control animals. However, i.c.v. pretreatment with gliquidone (0.4-1.6 micrograms/mouse), glipizide (2.5-10 micrograms/mouse), glibenclamide (10-40 micrograms/mouse) or tolbutamide (20-80 micrograms/mouse) dose dependently antagonized morphine-induced antinociception approximately equieffectively, the only difference being in potency: gliquidoneglipizideglibenclamidetolbutamide. This effect of sulfonylureas was very specific, since none antagonized the antinociception elicited by U50488H even at doses twice as great as the dose that induced maximum antagonism of morphine antinociception. Because morphine, but not U50488H, opens K+ channels in neurons and because the order of potency of the different sulfonylureas for blocking ATP-dependent K+ channels in neurons and for antagonizing morphine antinociception is the same, we suggest that morphine antinociception is mediated by the opening of ATP-dependent K+ channels.

1. The actions of the trivalent cation, gadolinium (Gd3+), were studied on frog isolated neuromuscular preparations by conventional electrophysiological techniques. 2. Gd3+ (450 microM) applied to normal or formamide-treated cutaneous pectoris nerve-muscle preparations induced, after a short delay, a complete block of neuromuscular transmission. The reversibility of the effect was dependent on the time of exposure. 3. Gd3+ (5-450 microM) had no consistent effect on the resting membrane potential of the muscle fibres. 4. Gd3+ (5-40 microM) applied to preparations equilibrated in solutions containing high Mg2+ and low Ca2+ reduced the mean quantal content of endplate potentials (e.p.ps) in a dose-dependent manner. Under those conditions, 3,4-diaminopyridine (10 microM) consistently reversed the depression of evoked quantal release. 5. The calcium current entering motor nerve terminals, revealed after blocking presynaptic potassium currents with tetraethylammonium (10 mM) in the presence of elevated extracellular Ca2+ (8 mM), was markedly reduced by Gd3+ (0.2-0.5 mM). 6. Gd3+ (40-200 microM) increased the frequency of spontaneous miniature endplate potentials (m.e.p.ps) in junctions bathed either in normal Ringer solution or in a nominally Ca(2+)-free medium supplemented with 0.7 microM tetrodotoxin. This effect may be due to Gd3+ entry into the nerve endings since it is not reversed upon removal of extracellular Gd3+ with chelators (1 mM EGTA or EDTA). Gd3+ also enhanced the frequency of me.p.ps appearing after each nerve stimulus in junctions bathed in a medium containing high Mg2+ and low Ca2+. 7. Gd3+, in concentrations higher than 100 microM, decreased reversibly the amplitude of m.e.p.ps suggesting a postsynaptic action. 8. It is concluded that the block of nerve-impulse evoked quantal release caused by Gd3 + is related to its ability to block the calcium current entering the nerve endings, supporting the view that Gd3 + blocks N-type Ca2+ channels; while the enhancement of spontaneous quantal release is probably the result of Gd3 + entry into motor nerve endings. Besides its dual prejunctional effects on quantal release it is suggested that Gd3 + exerts a postsynaptic action on the endplate acetylcholine receptor-channel complex.

Effects of two potassium chanel openers, cromakalim and pinacidil, on pentylenetetrazole-induced seizures in vivo

We showed that glibenclamide, a blocker of ATP-dependent potassium channels in the CNS, antagonizes morphine-induced analgesia in mice

The effects of calcium and the calcium channel stimulant Bay k 8644 on neomycin-induced neuromuscular blockade were evaluated using rat phrenic nerve-hemidiaphragm preparations in vitro. neomycin showed maximum potency in inducing neuromuscular blockade when the calcium concentration in the bath was 1 mM. Higher calcium concentrations (1.5, 2 and 4 mM) produced a gradual decrease in neomycin potency, manifested as a progressive shift to the right of neomycin concentration-response curves. Bay k 8644 (0.1 and 1 microM) did not significantly modify indirectly elicited diaphragm contractions per se, nor did it antagonize neomycin-induced neuromuscular blockade. A higher concentration of Bay k 8644 (10 microM) antagonized indirectly elicited contractions. In conclusion, our results show that Bay k 8644, at concentrations causing calcium channel stimulation at the cardiac and vascular level, did not exert stimulant effects in a nerve-skeletal muscle preparation, suggesting that its action may be tissue-selective to a certain degree.