Effects of Ketamine on Postoperative Pain After Remifentanil-Based Anesthesia for Major and Minor Surgery in Adults: A Systematic Review and Meta-Analysis.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been postulated as an adjuvant analgesic for preventing remifentanil-induced hyperalgesia after surgery. This systematic review and meta-analysis aims to assess the effectiveness of ketamine [racemic mixture and S-(+)-ketamine] in reducing morphine consumption and pain intensity scores after remifentanil-based general anesthesia. We performed a literature search of the PubMed, Web of Science, Scopus, Cochrane, and EMBASE databases in June 2017 and selected randomized controlled trials using predefined inclusion and exclusion criteria. To minimize confounding and heterogeneity, studies of NMDA receptor antagonists other than ketamine were excluded and the selected studies were grouped into those assessing minor or major surgery. Methodological quality was evaluated with the PEDro and JADA scales. The data were extracted and meta-analyses were performed where possible. Twelve RCTs involving 156 adults who underwent minor surgery and 413 adults who underwent major surgery were included in the meta-analysis. When used as an adjuvant to morphine, ketamine reduced postoperative morphine consumption in the first 24 h and postoperative pain intensity in the first 2 h in the minor and major surgery groups. It was also associated with significantly reduced pain intensity in the first 24 h in the minor surgery group. Time to the first rescue analgesia was longer in patients who received ketamine and underwent major surgery. No significant differences in the incidence of ketamine-related adverse effects were observed among patients in the intervention group and controls. This systematic review and meta-analysis show that low-dose (≤0.5 mg/kg for iv bolus or ≤5 µg/kg/min for iv perfusion) of ketamine reduces postoperative morphine consumption and pain intensity without increasing the incidence of adverse effects.

Evaluation of pain associated with chronic venous insufficiency in Spanish postmenopausal women.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Changes in morphine-induced activation of cerebral Na(+),K(+)-ATPase during morphine tolerance: biochemical and behavioral consequences.

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, 45mg/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±0.10µM) than in synaptosomes from morphine-naive mice (EC(50)=0.69±0.12µM). 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 10ng/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.

Sigma-1 receptors do not regulate calcium influx through voltage-dependent calcium channels in mouse brain synaptosomes.

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.

[The effectiveness of levetiracetam in the treatment of neuropathic pain]. / Eficacia del levetiracetam en el tratamiento del dolor neuropático.

INTRODUCTION: 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. AIM: To analyse the effectiveness of levetiracetam as an analgesic in the treatment of neuropathic pain by means of a systematic review of the literature. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Eficacia del levetiracetam en el tratamiento del dolor neuropático / The effectiveness of levetiracetam in the treatment of neuropathic pain

Introducción. El tratamiento farmacológico es la primera opción que se debe considerar en el tratamiento del dolor neuropático, en el que los antiepilépticos ocupan un lugar destacado. El levetiracetam es un antiepiléptico de última generación que ha mostrado actividad antinociceptiva en modelos experimentales de dolor y eficacia clínica analgésica en series de pacientes con dolor neuropático. Objetivo. Analizar la eficacia analgésica del levetiracetam en el tratamiento del dolor neuropático mediante una revisión sistemática de la bibliografía.Pacientes y métodos. Se ha utilizado la base de datos Medline/PubMed. Los criterios de búsqueda reunieron tres elementos fundamentales: levetiracetam, dolor neuropático y pacientes. Se han identificado los estudios hasta el 31 de enero de 2011. Los estudios seleccionados se sometieron a un análisis de calidad según la escala Physiotherapy Evidence Database (0-10). Resultados. Se seleccionaron tres series de casos, dos estudios pilotos abiertos y no controlados y cuatro ensayos clínicos aleatorizados (ECA). Sólo los ECA reunieron criterios de calidad aceptables. La etiología del dolor neuropático era diferente en los distintos ECA analizados. El levetiracetam mostró eficacia en el tratamiento del dolor neuropático en los estudios con calidad metodológica baja (series de casos y estudios pilotos) y en un ECA dirigido a pacientes con dolor neuropático central debido a esclerosis múltiple. onclusiones. Hay escasos ensayos clínicos de calidad metodológica alta que evalúen la eficacia del levetiracetam en el tratamiento del dolor neuropático y la mayoría de ellos no demuestra beneficio en relación con el placebo (AU)

Introduction. 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. Aim. To analyse the effectiveness of levetiracetam as an analgesic in the treatment of neuropathic pain by means of a systematic review of the literature. Patients and methods. 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). Results. 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 dueto multiple sclerosis. Conclusions. 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 (AU)

Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice.

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.

Antagonism by haloperidol and its metabolites of mechanical hypersensitivity induced by intraplantar capsaicin in mice: role of sigma-1 receptors.

RATIONALE: We evaluated the effects of haloperidol and its metabolites on capsaicin-induced mechanical hypersensitivity (allodynia) and on nociceptive pain induced by punctate mechanical stimuli in mice. RESULTS: Subcutaneous administration of haloperidol or its metabolites I or II (reduced haloperidol) dose-dependently reversed capsaicin-induced (1 microg, intraplantar) mechanical hypersensitivity of the hind paw (stimulated with a nonpainful, 0.5-g force, punctate stimulus). The order of potency of these drugs to induce antiallodynic effects was the order of their affinity for brain sigma-1 (sigma(1)) receptor ([(3)H](+)-pentazocine-labeled). Antiallodynic activity of haloperidol and its metabolites was dose-dependently prevented by the selective sigma(1) receptor agonist PRE-084, but not by naloxone. These results suggest the involvement of sigma(1) receptors, but discard any role of the endogenous opioid system, on the antiallodynic effects. Dopamine receptor antagonism also appears unlikely to be involved in these effects, since the D(2)/D(3) receptor antagonist (-)-sulpiride, which had no affinity for sigma(1) receptors, showed no antiallodynic effect. None of these drugs modified hind-paw withdrawal after a painful (4 g force) punctate mechanical stimulus in noncapsaicin-sensitized animals. As expected, the control drug gabapentin showed antiallodynic but not antinociceptive activity, whereas clonidine exhibited both activities and rofecoxib, used as negative control, showed neither. CONCLUSION: These results show that haloperidol and its metabolites I and II produce antiallodynic but not antinociceptive effects against punctate mechanical stimuli and suggest that their antiallodynic effect may be due to blockade of sigma(1) receptors but not to dopamine receptor antagonism.

Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice.

We evaluated the effect of low doses of systemically administered tetrodotoxin (TTX) on the development and expression of neuropathic pain induced by paclitaxel in mice. Treatment with paclitaxel (2mg/kg, i.p., once daily during 5 days) produced long-lasting (2-4 weeks) heat hyperalgesia (plantar test), mechanical allodynia (electronic Von Frey test) and cold allodynia (acetone drop method), with maximum effects observed on days 7, 10 and 10-14, respectively. Acute subcutaneous treatment with 1 or 3 microg/kg of TTX reduced the expression of mechanical allodynia, whereas higher doses (3 or 6 microg/kg) were required to reduce the expression of cold allodynia and heat hyperalgesia. In contrast, TTX (3 or 6 microg/kg, s.c.) did not affect the response to the same thermal and mechanical stimuli in control animals, which indicates that the antihyperalgesic and antiallodynic effects of TTX were not due to unspecific inhibition of the perception of these stimuli. Administration of TTX (6 microg/kg, s.c.) 30 min before each of the 5 doses of paclitaxel did not modify the development of heat hyperalgesia produced by the antineoplastic, but abolished the development of mechanical and cold allodynia. Coadministration of a lower dose of TTX (3 microg/kg) also prevented the development of mechanical allodynia. No signs of TTX-induced toxicity or motor incoordination were observed. These data suggest that low doses of TTX can be useful to prevent and treat paclitaxel-induced neuropathic pain, and that TTX-sensitive subtypes of sodium channels play a role in the pathogenesis of chemotherapy-induced neuropathic pain.

Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells.

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 antinociceptive effect of morphine is reversed by okadaic acid in morphine-naive but not in morphine-tolerant mice.

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.

Differences in the allosteric modulation by phenytoin of the binding properties of the sigma1 ligands [3H](+)-pentazocine and [3H]NE-100.

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.

Inhibitors of serine/threonine protein phosphatases antagonize the antinociception induced by agonists of alpha 2 adrenoceptors and GABAB but not kappa-opioid receptors in the tail flick test in mice.

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.

Phenytoin differentially modulates the affinity of agonist and antagonist ligands for sigma 1 receptors of guinea pig brain.

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.

Role of Na(+), K(+)-ATPase in morphine-induced antinociception.

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 1-1000, and digitoxin at 10-10000 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.

Effects of serine/threonine protein phosphatase inhibitors on morphine-induced antinociception in the tail flick test in mice.

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.