Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation.

Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

Population pharmacokinetics of carboplatin, etoposide and melphalan in children: a re-evaluation of paediatric dosing formulas for carboplatin in patients with normal or mild impairment of renal function.

AIMS: Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration-time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high-risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols. METHODS: Data on children receiving high-dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4 mg ml-1 ·min) would be achieved using the paediatric Newell formula, modified Calvert formula and weight-based dosing. RESULTS: Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100 ml min-1 1.73 m-2 but not for those with a GFR ≥100 ml min-1 1.73 m-2 . A weight-based dosing regimen of 50 mg kg-1 achieved the target AUC more consistently than the other formulas, regardless of renal function. CONCLUSIONS: GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model-based approach validates the use of weight-based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.

Long-term impact of legume-inclusive diversification and nutrient management practices on phosphorus dynamics in alkaline Fluvisol.

An insight into the dynamics of soil phosphorus (P) pools with long-term cropping/management practices would help in designing efficient and sustainable management module(s). The study aimed to investigate the long-term impact of diversified rice-based rotations and variable nutrient management practices on the dynamic composition of P pools and their influence on systems' base-crop productivity in an alkaline soil of Indo-Gangetic plain (Fluvisol). Treatments consisted of four rotations [rice-wheat (R-W), rice-wheat-mungbean (R-W-Mb), rice-wheat-rice-chickpea (R-W-R-C), rice-chickpea (R-C)] each with three nutrient treatments [control (CT), integrated nutrient management (INM), sole-chemical fertilizers (CF)]. Notably, R-C exhibited higher levels of bioavailable-P (soluble-P, Ca2-P, labile-Po), particularly in subsurface soil depth (0.2-0.4 m) compared to other rotations. Likewise, the inclusion of chickpea every alternate year (R-W-R-C) resulted in higher Ca2-P (40%), labile-Pi (15%), labile-Po (11%), and moderately labile Po (8%) compared to R-W rotation demonstrating an increased significance of chickpea in maintaining a favorable soil P regime in alkaline soil. Both R-C and R-W-R-C reduced the surface-to-subsurface depth ratio (SSBR) of soluble-P and Ca2-P while increasing the ratio for microbial biomass P. Even with a suboptimal fertilizer-P rate, INM significantly increased soluble-P (4-33%), labile-Po (13-17%), microbial biomass P (10-26%), moderately labile-Po (4-17%) compared to CF and exhibited higher SSBR values. Correlation analysis demonstrated the substantial influence of very-labile carbon, microbial and phosphatase activities on P availability. The treatment-induced changes in labile-P pools significantly influenced rice (base-crop) yields. In conclusion, chickpea-inclusive diversification and INM could be a sustainable approach to enhance P bioavailability and crop productivity in tropical rice soils.

Long-term impact of pulses and organic amendments inclusion in cropping system on soil physical and chemical properties.

Mono-cropping of maize-wheat, mechanical disintegration of soils, and continuous chemical fertilization have deteriorated soil health in the Indo-Gangetic Plains. We studied the long-term impact of pulse-based cropping systems with integrated nutrient management on soil physical and chemical properties and yield sustainability. We evaluated four different cropping systems: (1) maize-wheat (M-W), (2) maize-wheat-mungbean (M-W-Mb), (3) maize-wheat-maize-chickpea (M-W-M-C), (4) pigeonpea-wheat (P-W) each with three degrees of soil fertilization techniques: (1) unfertilized control (CT), (2) inorganic fertilization (RDF), and (3) integrated nutrient management (INM). The field experiment was undertaken in a split-plot design with three replications each year with a fixed layout. P-W and M-W-Mb systems enhanced soil properties such as volume expansion by 9-25% and porosity by 7-9% (p < 0.05) more than M-W, respectively. P-W and M-W-Mb increased soil organic carbon by 25-42% and 12-50% over M-W (RDF). P-W system enhanced water holding capacity and gravimetric moisture content by 10 and 11% (p < 0.05) than M-W. Pulse-based systems (P-W and M-W-Mb) had higher available nitrogen (8-11%), phosphorus (42-73%), and potassium (8-12%) over M-W (p < 0.05). M-W-Mb increased 26% maize yield and 21% wheat yield over M-W (p < 0.05) at the thirteenth crop cycle. P-W system had a higher sustainable yield index (p < 0.05) of wheat over the M-W. Thus, pulse inclusion in the cropping system in combination with INM can enhance physical and chemical properties vis-à-vis sustainable yield index over the cereal-cereal system.

Elephants also like coffee: trends and drivers of human-elephant conflicts in coffee agroforestry landscapes of Kodagu, Western Ghats, India.

Kodagu district produces 2% of the world's coffee, in complex, multistoried agroforestry systems. The forests of the district harbour a large population of the Asian elephant (Elephas maximus). The combined effects of high elephant density and major landscape changes due to the expansion of coffee cultivation are the cause of human-elephant conflicts (HEC). Mitigation strategies, including electric fences and compensation schemes implemented by the Forest Department have met with limited success. Building on previous studies in the area, we assessed current spatial and temporal trends of conflict, analysed local stakeholders' perceptions and identified factors driving elephants into the estates. Our study, initiated in May 2007, shows that the intensity of HEC has increased over the last 10 years, exhibiting new seasonal patterns. Conflict maps and the lack of correlation between physical features of the coffee plantations and elephant visits suggest elephants move along corridors between the eastern and western forests of the district, opportunistically foraging when crossing the plantations. Dung analyses indicate elephants have selectively included ripe coffee berries in their diet. This is, to our knowledge, the first report of wild elephants feeding on coffee berries. If this new behaviour spreads through the population, it will compound an already severe conflict situation. The behavioural plasticity, the multiplicity of stakeholders involved, the difficulty in defining the problem and the limits of technical solutions already proposed suggest that HEC in Kodagu has the ingredients of a "wicked" problem whose resolution will require more shared understanding and problem solving work amongst the stakeholders.

Erratum to: Elephants also like coffee: Trends and drivers of human-elephant conflicts in coffee agroforestry landscapes of Kodagu, Western Ghats, India.

Kodagu district produces 2% of the world's coffee, in complex, multistoried agroforestry systems. The forests of the district harbour a large population of the Asian elephant (Elephas maximus). The combined effects of high elephant density and major landscape changes due to the expansion of coffee cultivation are the cause of human-elephant conflicts (HEC). Mitigation strategies, including electric fences and compensation schemes implemented by the Forest Department have met with limited success. Building on previous studies in the area, we assessed current spatial and temporal trends of conflict, analysed local stakeholders' perceptions and identified factors driving elephants into the estates. Our study, initiated in May 2007, shows that the intensity of HEC has increased over the last 10 years, exhibiting new seasonal patterns. Conflict maps and the lack of correlation between physical features of the coffee plantations and elephant visits suggest elephants move along corridors between the eastern and western forests of the district, opportunistically foraging when crossing the plantations. Dung analyses indicate elephants have selectively included ripe coffee berries in their diet. This is, to our knowledge, the first report of wild elephants feeding on coffee berries. If this new behaviour spreads through the population, it will compound an already severe conflict situation. The behavioural plasticity, the multiplicity of stakeholders involved, the difficulty in defining the problem and the limits of technical solutions already proposed suggest that HEC in Kodagu has the ingredients of a "wicked" problem whose resolution will require more shared understanding and problem solving work amongst the stakeholders.

Expansion of hay production and marketing in Brazil.

In the last decade, advances in Brazilian hay production showed that the country has the potential to produce bulky dehydrated fodder. For many years, the Brazilian hay production scientific knowledge had been based on temperate climate species, even though the best hay material are tropical grasses, as Tifton 85 Bermudagrass. Researches that focused on the comprehension of yield systems, biochemical processes, physiology, composition, and nutritional quality of tropical species under dehydration and conservation have become important to hay yield in Brazil. Therefore, this literature review aimed to discuss the hay research contribution in tropical conditions and its reflex on the production and commercialization of hay in Brazil. This review was based on database research with key-words defined in a period between 1960 and 2021, which resulted in 33 articles. Each article had the strengths and weaknesses, opportunities, and threats classified according to the SWOT matrix. Articles related to the haymaking system with tropical forage and the effects on nutritional value, sanitary quality, and factors that influence the dehydration period in the field and storage were listed in this paper. Based on the literature, the conclusion is that Brazil has elevated hay yield potential with high nutritional and sanitary quality of tropical species due to the weather conditions that allow fast dehydration and, also, the availability of residual wastewater as fertilization and machinery appropriated. Brazilian haymaking and commercialization are in an expansion process with economic return as national and international trade. Further challenges: to obtain a constant annual hay supply and the transport viability to markets distant from the production center.

Population pharmacokinetics of acyclovir in children and young people with malignancy after administration of intravenous acyclovir or oral valacyclovir.

Acyclovir is effective in the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. The aim of this study was to characterize the population pharmacokinetics of acyclovir observed following treatment with intravenous acyclovir and oral valacyclovir (valaciclovir) in young people with malignancy. Plasma acyclovir concentration-time data were collected from 43 patients (age range, 9 months to 20 years) who had been given multiple doses of acyclovir (5 mg/kg of body weight) and/or valacyclovir (10 mg/kg). Nonlinear mixed-effect modeling was employed to analyze acyclovir population pharmacokinetics and identify influential covariates. Simulations (n = 1,000) were conducted to explore the ability of the current doses to maintain acyclovir concentrations above the recommended 50% inhibitory concentration for HSV or VZV (0.56 mg/liter or 1.125 mg/liter, respectively) for more than 12 h. A one-compartment pharmacokinetic model with first-order elimination best described the acyclovir concentration-time data. The population mean estimates for clearance (CL), volume of distribution (V), absorption rate (k(a)), and bioavailability (F) were 3.55 liters/h, 7.36 liters, 0.63 h(-1), and 0.60, respectively. Inclusion of body weight and estimated creatinine CL (CL(CR)) in the final model reduced the interindividual variabilities in CL and V from 61% to 24% and from 75% to 36%, respectively. Simulations revealed that with the use of the current doses, maximal efficacy can be achieved in over 45% of patients weighing 25 to 50 kg and with CL(CR) levels of 2.0 to 4.0 liters/h/m(2), but only in a much smaller proportion of patients, with low weights (10 kg) and high CL(CR)s (5.5 liters/h/m(2)), suggesting that higher doses are required for this subgroup. This validated population pharmacokinetic model for acyclovir may be used to develop dosing guidelines for safe and effective antiviral therapy in young people with malignancy.

HPLC-UV assay for monitoring total and unbound mycophenolic acid concentrations in children.

A simple, accurate and sensitive HPLC method was developed for measuring total and unbound mycophenolic acid (MPA) in human plasma. Total MPA was extracted by protein precipitation and ultrafiltration was used to assess unbound MPA concentrations. The supernatant (20 microL) or ultrafiltrate (100 microL) was injected onto a C(18) HPLC column with a mobile phase of 0.05 m sodium phosphate buffer (pH 2.31)-acetonitrile (55:45, v/v for total MPA; 50:50 for unbound MPA) with UV detection at 254 nm. The extraction recovery was over 93% and reproducible. The assay was linear over the concentration range of 0.07-50 mg/L for total MPA and 4-1500 microg/L for unbound MPA. Intra- and inter-day assay reproducibility was less than 10%. Detection limits were 0.04 mg/L and 2 microg/L for total and unbound MPA, respectively. The assay utility was established in samples collected from five paediatric bone marrow transplant recipients who were receiving intravenous doses of mycophenolate mofetil. In these patients MPA concentrations ranged from 0.07 to 7.83 mg/L and unbound drug concentrations ranged from 2.1 to 107.5 microg/L. This method can be effectively applied to MPA pharmacokinetics in paediatric patients.

Interpretation of alpha-fetoprotein concentrations in cerebrospinal fluid of infants.

BACKGROUND: There are no published reference intervals for concentrations of alpha-fetoprotein (AFP) in the cerebrospinal fluid (CSF) of normal infants. The presence of abnormal concentrations of AFP in plasma or CSF may indicate the presence of a teratoma or a germ cell tumour with yolk sac elements. We measured CSF AFP in infants who did not have malignancy in order to determine its reference intervals. METHODS: AFP was measured in the CSF and/or plasma in 128 infants. Of these, 91 infants had CSF AFP measurements, 94 infants had plasma AFP measurements and in 60 infants AFP concentrations were determined in paired CSF and plasma samples. The patients ranged in age from 1 to 110 days. Both CSF and plasma AFP concentrations were measured by a microparticle enzyme immunoassay using an AxSYM analyser. RESULTS: Using ages corrected for prematurity, the median CSF AFP concentration for babies -69 to 31 days old was 61 kIU/L (5th-95th centile: 2-889 kIU/L), while the median CSF AFP concentration for infants 32 to 110 days was 1.2 kIU/L (5th-95th centile: 0.1-12.5 kIU/L). By age 6 weeks, the concentrations were close to those found in adult plasma and all CSF AFP concentrations from infants with a corrected age over 2 months were <3 kIU/L. CONCLUSION: We have defined reference intervals for CSF AFP concentrations in infants. These results may assist in the diagnosis of CNS tumours, particularly congenital CNS tumours containing yolk sac elements.

Promising Role of Melatonin as Neuroprotectant in Neurodegenerative Pathology.

Melatonin treatment showed a potent neuroprotective action in experimental models and in clinical studies. However, the entire disease prevention is not observed with melatonin treatment. Therefore, findings have suggested its future use in combination therapies for neurological diseases. Several studies have showed its free radical scavenging, antioxidant property, antiapoptotic activity, and its action towards enhanced mitochondrial function. It has direct and indirect effects on mitochondrial functions. Neurodegenerative disease pathology includes the impaired mitochondrial functions and apoptotic death of neurons due to energy crisis which could be prevented with antiapoptotic activity of melatonin. However, for the therapeutic use of melatonin, researchers also need to pay attention towards the various intermediary events taking place in apoptotic death of neurons during disease pathology. Age-related neurological diseases include the decreased level of melatonin in neuronal death. Therefore, it is worthwhile to discuss about the different functions of melatonin in aspect of its antioxidative property, its role in the enhancement of mitochondrial function, and its antiapoptotic attributes. This review summarizes the reports to date showing the potent role of melatonin in experimental models and clinical trials and discussing the employment of melatonin as future potent neuroprotective agent.

6-Hydroxydopamine and lipopolysaccharides induced DNA damage in astrocytes: involvement of nitric oxide and mitochondria.

The present study was conducted to investigate the effect of the neurotoxins 6-hydroxydopamine and lipopolysaccharide on astrocytes. Rat astrocyte C6 cells were treated with different concentration of 6-hydroxydopamine (6-OHDA)/lipopolysaccharides (LPS) for 24 h. Both neurotoxins significantly decreased the viability of astrocytes, augmented the expression of inducible nitric oxide synthase (iNOS) and the astrocyte marker--glial fibrillar acidic protein. A significantly decreased mitochondrial dehydrogenase activity, mitochondrial membrane potential, augmented reactive oxygen species (ROS) level, caspase-3 mRNA level, chromatin condensation and DNA damage was observed in 6-OHDA/LPS treated astroglial cells. 6-OHDA/LPS treatment also caused the significantly increased expression of iNOS and nitrite level. Findings showed that 6-OHDA/LPS treatment caused mitochondrial dysfunction mediated death of astrocytes, which significantly involve the nitric oxide. Since we have observed significantly increased level of iNOS along with mitochondrial impairment and apoptotic cell death in astrocytes, therefore to validate the role of iNOS, the cells were co-treated with iNOS inhibitor aminoguanidine (AG, 100 µM). Co-treatment of AG significantly attenuated the 6-OHDA/LPS induced cell death, mitochondrial activity, augmented ROS level, chromatin condensation and DNA damage. GFAP and caspase-3 expression were also inhibited with co-treatment of AG, although the extent of inhibition was different in both experimental sets. In conclusion, the findings showed that iNOS mediated increased level of nitric oxide acts as a key regulatory molecule in 6-OHDA/LPS induced mitochondrial dysfunction, DNA damage and apoptotic death of astrocytes.

Concentration-response relationships of disopyramide in patients with ventricular tachycardia.

The protein binding of disopyramide is altered when concentration is increased within the therapeutic range. A wide range of free concentrations may be produced at a given total concentration. The present study assessed whether intracardiac electrophysiologic responses to disopyramide related better to free or to total concentration. Intravenous infusions of disopyramide were evaluated in 17 patients with inducible sustained ventricular tachycardia. The first maintenance infusion produced total serum concentrations of 11.7 +/- 2 mumols/L, and no significant increase occurred at higher-dose infusions. However, free concentrations during the first and second maintenance infusions were significantly different at 5.3 +/- 1 mumols/L and 6.8 +/- 1 mumols/L, respectively. Free fraction also increased significantly, from 45% +/- 8% to 50% +/- 7%. Overall change in QTc interval and ventricular tachycardia cycle length correlated with free concentration but not with total concentration. This study showed that some intracardiac measurements correlate with free concentration but that none correlate with total concentration.

Busulphan given as four single daily doses of 150 mg/m2 is safe and effective in children of all ages.

We examined the effects of busulphan (BU) dose and patient age on toxicity and outcome in 63 children with acute leukaemia given BUCY prior to allogeneic or autologous BMT. BU was administered as four single daily oral doses, based either on weight (4 x 4 mg/kg) or surface area (4 x 150 mg/m2). BU pharmacokinetic analysis was not used to dose adjust. The average daily (mg/kg) BU dose was 43% higher for the group given 150 mg/m2 compared to the 4 mg/kg dose group. This produced a median BU AUC 61% higher than with the 4 mg/kg dose. Only one child did not achieve full allogeneic donor engraftment. Regimen-related toxicity was low. Although younger children had faster BU clearance, the 4 x 150 mg/m2 dose ensured equivalent systemic exposure to BU, and resulted in a high frequency of engraftment without a significant increase in serious toxicity. BU, given as four single daily doses of 150 mg/m2, is appropriate and safe in all age groups of children. Given the reliable pharmacokinetics, low toxicity and high rate of allogeneic engraftment, there is no need for routine pharmacokinetic monitoring or dose modifications. This dosage regimen may be applicable for use with i.v. BU.

Evidence for central histaminergic mechanism in foot shock aggression.

The role of central histaminergic system in foot shock induced aggression was studied in mice. Histamine administered by intracerebral (IC) injection (25-200 micrograms) produced a significant increase in fighting episodes in a dose dependent manner. It was observed that mepyramine (H1 blocker) given intraperitoneally (IP) significantly increased and metiamide (H2 blocker) given IC decreased significantly the fighting response. To determine the nature of receptors involved in histamine induced facilitation of aggressive behaviour, histamine was administered IC in mice pretreated with mepyramine or metiamide. Mepyramine pretreatment further increased the facilitatory effect of histamine while metiamide blocked the enhancement of aggressiveness by histamine. Combined pretreatment with metiamide and mepyramine decreased significantly the fighting counts which remained unaffected after histamine. Haloperidol did not block the enhancement of aggression by histamine or mepyramine. However, atropine pretreatment partially inhibited the histamine induced increase in the fighting counts. Results of pretreatment with metiamide and atropine were similar to those obtained with pretreatment of metiamide and mepyramine. Metiamide alone or in combination with atropine failed to affect the facilitatory effect of amphetamine on the foot-shock aggression. It is concluded that central histamine H2 receptors have a facilitatory role and H1 receptors an inhibitory role on aggressive behaviour in mice induced by foot-shock. Since histamine per se had a facilitatory effect on foot-shock induced aggression, the central H2 receptors seem to dominate over the H1 receptors.

Novel effects of MPTP: MAO-B unrelated opioidergic activity in mice.

The presence of opioidergic activity after i.p. injection of N-methyl-4-phenyl tetrahydropyridine (MPTP) has been investigated in albino mice by studying analgesia and the Straub reaction. MPTP (6.25-25 mg kg-1) produced a dose-related analgesic response and Straub reaction. These effects of MPTP were effectively antagonized by prior naloxone treatment but remained unaffected after the MAO-B inhibitor deprenyl. MPTP thus possesses significant opioidergic activity and this, unlike its neurotoxic actions, does not appear to be dependent on oxidative conversion to MPP+ (1-methyl-4-phenyl pyridinium).

Cardiovascular adaptations in Andean natives after 6 wk of exposure to sea level.

Six male Quechua Indians (34.0 +/- 1.1 yr, 159.5 +/- 2.1 cm, 60.5 +/- 1.6 kg), life-long residents of La Raya, Peru (4,350-m altitude with an average barometric pressure of 460 Torr), were studied using noninvasive methods to determine the structural and functional changes in the cardiovascular system in response to a 6-wk deacclimation period at sea level. Cardiac output, stroke volume, and left ventricular ejection fractions were determined using radionuclide angiographic techniques at rest and during exercise on a cycle ergometer at 40, 60, and 90% of a previously determined maximal O2 consumption. Subjects at rest were subjected to two-dimensional and M-mode echocardiograms and a standard 12-lead electrocardiogram. Hemoglobin and hematocrit were measured on arrival at sea level by use of a Coulter Stacker S+ analyzer. After a 6-wk deacclimation period, all variables were remeasured using the identical methodology. Hemoglobin values decreased significantly over the deacclimation period (15.7 +/- 1.1 to 13.5 +/- 1.2 g/dl; P less than 0.01). The results indicate that the removal of these high-altitude-adapted natives from 4,300 m to sea level for 6 wk results in only minor changes to the cardiac structure and function as measured by these noninvasive techniques.

Effect of electroconvulsive shock on central cholinergic (muscarinic) receptors.

Sensitivity of central cholinergic (muscarinic) receptors was studied in rats after application of single and repeated (once daily for 7 days) electroconvulsive shocks (ECS). Oxotremorine-induced tremor was significantly enhanced after single as well as chronic exposure to ECS; [3H]QNB binding in frontal cortex was also significantly increased by chronic ECS. The results indicate that ECS develops supersensitivity in central muscarinic receptors.

Morphine-induced straub tail response: mediated by central mu2-opioid receptor.

The opioid receptor mechanism involved in the morphine induced straub tail response was investigated in mice. Morphine (2.5, 5, 10 and 20 mg/kg s.c.) produced a dose dependent straub tail response and analgesia (hot plate test). Naloxone (5 mg/kg s.c.) and the mu-opioid receptor antagonist beta-funaltrexamine (10 micrograms i.c.v.) blocked both the straub tail response and analgesia while the mu 1-opioid receptor selective antagonist naloxonazine (35 mg/kg s.c.) blocked only analgesia and did not affect the straub tail response. Morphine (20 micrograms) administered by the i.c.v. route also produced the straub tail response as well as analgesia. Pretreatment with naloxonazine (35 mg/kg s.c.) antagonised i.c.v. administered morphine induced analgesia while the straub tail response was not affected. The results indicate that the morphine induced straub analgesia while the straub tail response was not affected. The results indicate that the morphine induced straub tail response is mediated by central mu 2-opioid receptors.