Development Of Acute Tolerance Research Articles

Relationship between intraoperative requirement for anesthetics and postoperative analgesic consumption in laparoscopic colectomy: a randomized controlled double-blinded study.

This study investigated the relationship between intraoperative requirement for an inhalational anesthetic (sevoflurane) or an opioid (remifentanil) and postoperative analgesic consumption. The study included 200 adult patients undergoing elective laparoscopic colectomy. In the sevoflurane group, the effect-site concentration of remifentanil was fixed at 1.0 ng/ml, while the inspiratory sevoflurane concentration was adjusted to maintain an appropriate anesthetic depth. In the remifentanil group, the end-expiratory sevoflurane concentration was fixed at 1.0 vol.%, and the remifentanil concentration was adjusted. Pain scores and cumulative postoperative analgesic consumptions were evaluated at 2, 6, 24, and 48 h after surgery. Average end-tidal concentration of sevoflurane and effect-site concentration of remifentanil were 2.0 ± 0.4 vol.% and 3.9 ± 1.4 ng/ml in the sevoflurane and remifentanil groups, respectively. Cumulative postoperative analgesic consumption at 48 h postoperatively was 55 ± 26 ml in the sevoflurane group and 57 ± 33 ml in the remifentanil group. In the remifentanil group, the postoperative cumulative analgesic consumptions at 2 and 6 h were positively correlated with intraoperative remifentanil requirements (2 h: r = 0.36, P < 0.001; 6 h: r = 0.38, P < 0.001). However, there was no significant correlation in the sevoflurane group (r = 0.04, P = 0.691). The amount of intraoperative requirement of short acting opioid, remifentanil, is correlated with postoperative analgesic consumption within postoperative 6 h. It may be contributed by the development of acute opioid tolerance. However, intraoperative sevoflurane requirement had no effect on postoperative analgesic consumption.

Selective PDE4B and PDE4D inhibitors produce distinct behavioral responses to ethanol and GABAergic drugs in mice

Apremilast is a phosphodiesterase (PDE) type 4 inhibitor that is nonselective at subtypes PDE4A-D. It modulates ethanol and GABAergic responses via protein kinase A (PKA) phosphorylation of specific GABAA receptor subunits and has opposite effects on ethanol-induced ataxia in wild-type and GABAA β3-S408/409A knock-in mice. We hypothesized that these different effects are due to preferential actions at different PDE4 subtypes. To test this hypothesis, we compared effects of selective PDE4 inhibitors on responses to ethanol and GABAergic drugs in male and female C57BL/6J mice. The PDE4B inhibitor A33 accelerated recovery from ataxia induced by ethanol and diazepam but did not alter ataxia induced by propofol. The PDE4D inhibitor D159687 accelerated recovery from diazepam-induced ataxia but prolonged recovery from ethanol- and propofol-induced ataxia. A33 shortened, while D159687 prolonged, the sedative-hypnotic effects of ethanol. Both drugs shortened diazepam's sedative-hypnotic effects. The modulatory effects of A33 and D159687 were completely prevented by the PKA inhibitor H89. Only D159687 prevented development of acute functional tolerance to ethanol-induced ataxia. D159687 transiently reduced two-bottle choice drinking in male and female mice that had consumed ethanol for 3 weeks and transiently reduced two-bottle choice, every-other-day drinking in male mice. A33 did not alter ethanol drinking in either procedure. Neither drug altered binge-like ethanol consumption or blood ethanol clearance. Thus, D159687 produced behavioral effects similar to apremilast, although it produced a more transient and smaller reduction in drinking. These results indicate that PDE4D inhibition contributes to apremilast's ability to reduce ethanol drinking, whereas PDE4B inhibition is not involved.

Mice with high FGF21 serum levels had a reduced preference for morphine and an attenuated development of acute antinociceptive tolerance and physical dependence

Because of increased opioid misuse, there is a need to identify new targets for minimizing opioid tolerance, and physical and psychological dependence. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55 °C hot plate and the 55 °C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had a decrease in the development of acute analgesic tolerance, and the development of physical dependence, and morphine preference. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain patients to minimize tolerance development.

ALTERACIONES EN LA CONDUCCIÓN SIMULADA DE VEHÍCULOS, IMPULSIVIDAD Y ATENCIÓN EN LA FASE ASCENDENTE Y DESCENDENTE DE LA INTOXICACIÓN POR ALCOHOL

Objetivos. Se analizó el desarrollo de tolerancia aguda a los efectos del alcohol (dosis = 0.08%) sobre la capacidad de conducción de automotor – medida con un simulador -- y los efectos de esta dosis de alcohol sobre inhibición de respuesta en curso y procesos atencionales. Metodología. Los participantes (n = 56, edad= 22± 2.92 años) fueron distribuidos en un diseño factorial 2 (sexo [varón o mujer]) x 2 (tratamiento [alcohol o placebo]), con una medición pre-test y dos post-test. Cada medición post-test estuvo caracterizada por niveles similares de alcohol en aliento, correspondientes a la curva ascendente y descendente de la concentración de alcohol. Resultados. Análisis de varianza de medidas repetidas mostraron que quienes recibieron alcohol, comparados con quienes recibieron placebo, tuvieron más desvíos, excesos de velocidad y colisiones contra estructuras en ambos posts-test. Quienes recibieron alcohol exhibieron, al comparar las mediciones del post-test 2 con las del post-test 1, una cantidad similar de desvíos y colisiones contra estructuras, pero un aumento de excesos de velocidad. El alcohol afectó el proceso de atención en el post-test 1, pero no en el post-test 2. Discusión. El alcohol indujo, en las fases ascendente y descendente, deterioro en la capacidad de conducción, así como en atención e impulsividad. Se observó desarrollo de tolerancia aguda en los procesos atencionales. Estos resultados suman evidencia sobre los efectos negativos del alcohol en la conducción de vehículos y en procesos asociados a la conducción.

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

BackgroundSWI/SNF chromatin remodeling genes are required for normal acute responses to alcohol in C. elegans and are associated with alcohol use disorder in two human populations. In an effort to discover the downstream genes that are mediating this effect, we identified SWI/SNF-regulated genes in C. elegans.ResultsTo identify SWI/SNF-regulated genes in adults, we compared mRNA expression in wild type and swsn-1(os22ts) worms under conditions that produce inactive swsn-1 in mature cells. To identify SWI/SNF-regulated genes in neurons, we compared gene expression in swsn-9(ok1354) null mutant worms that harbor a neuronal rescue or a control construct. RNA sequencing was performed to an average depth of 25 million reads per sample using 50-base, paired-end reads. We found that 6813 transcripts were significantly differentially expressed between swsn-1(os22ts) mutants and wild-type worms and 2412 transcripts were significantly differentially expressed between swsn-9(ok1354) mutants and swsn-9(ok1354) mutants with neuronal rescue. We examined the intersection between these two datasets and identified 603 genes that were differentially expressed in the same direction in both comparisons; we defined these as SWI/SNF-regulated genes in neurons and in adults. Among the differentially expressed genes was cbp-1, a C. elegans homolog of the mammalian CBP/p300 family of histone acetyltransferases. CBP has been implicated in the epigenetic regulation in response to alcohol in animal models and a polymorphism in the human CBP gene, CREBBP, has been associated with alcohol-related phenotypes. We found that cbp-1 is required for the development of acute functional tolerance to alcohol in C. elegans.ConclusionsWe identified 603 transcripts that were regulated by two different SWI/SNF complex subunits in adults and in neurons. The SWI/SNF-regulated genes were highly enriched for genes involved in membrane rafts, suggesting an important role for this membrane microdomain in the acute alcohol response. Among the differentially expressed genes was cbp-1; CBP-1 homologs have been implicated in alcohol responses across phyla and we found that C. elegans cbp-1 was required for the acute alcohol response in worms.

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles.

The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.

Lithium reverses the effect of opioids on eNOS/nitric oxide pathway in human umbilical vein endothelial cells.

The main challenge of pain management with opioids is development of acute and chronic analgesic tolerance. Several studies on neuronal cells have focused on the molecular mechanisms involved in tolerance such as cyclic AMP (cAMP) activation, and nitric oxide (NO) pathway. However, the effects of opioids on non-neuronal cells and tolerance development have been poorly investigated. Lithium chloride is a glycogen synthase kinase 3β (GSK-3β) inhibitor and exert its effects through modulation of nitric oxide pathway. In this study we examined the effect of lithium on acute/chronic morphine and methadone administration in endothelial cells which express mu opioid receptors. Human umbilical vein endothelial cells (HUVECs) were treated with different doses of morphine, methadone, and lithium for six and 48h. Then we evaluated cell viability, nitrite and cyclic AMP levels, as well as the expression of endothelial nitric oxide synthase (eNOS) protein using Immunocytochemistry (ICC) assay and phosphorylated GSK-3β enzyme by western blot analysis in cells. Both chronic morphine and methadone treatment increased NO level and eNOS expression in HUVECs. Morphine induced cAMP overproduction after 48h exposure with cells. Lithium pretreatment (10mM) in both morphine and methadone received groups significantly reduced nitrite and cAMP levels as well as eNOS expression as compared to the control. The decreased amount of phospho GSK-3β due to the opioid exposure was increased following lithium treatment. Tolerance like pattern may occur in non-neuronal cells with opioid receptors and this study clearly revealed the attenuation of morphine and methadone tolerance like behavior by lithium treatment in HUVECs.

Neonatal ethanol exposure triggers apoptosis in the murine retrosplenial cortex: Role of inhibition of NMDA receptor-driven action potential firing

Exposure to ethanol during the last trimester equivalent of human pregnancy causes apoptotic neurodegeneration in the developing brain, an effect that is thought to be mediated, in part, by inhibition of NMDA receptors. However, NMDA receptors can rapidly adapt to the acute effects of ethanol and are ethanol resistant in some populations of developing neurons. Here, we characterized the effect of ethanol on NMDA and non-NMDA receptor-mediated synaptic transmission in the retrosplenial cortex (RSC), a brain region involved in the integration of different modalities of spatial information that is among the most sensitive regions to ethanol-induced neurodegeneration. A single 4-h exposure to ethanol vapor of 7-day-old transgenic mice that express the Venus fluorescent protein in interneurons triggered extensive apoptosis in the RSC. Slice electrophysiological recordings showed that bath-applied ethanol inhibits NMDA and non-NMDA receptor excitatory postsynaptic currents (EPSCs) in pyramidal neurons and interneurons; however, we found no evidence of acute tolerance development to this effect after the 4-h in-vivo ethanol vapor exposure. Acute bath application of ethanol reduced action potential firing evoked by synaptic stimulation to a greater extent in pyramidal neurons than interneurons. Submaximal inhibition of NMDA EPSCs, but not non-NMDA EPSCs, mimicked the acute effect of ethanol on synaptically-evoked action potential firing. These findings indicate that partial inhibition of NMDA receptors by ethanol has sizable effects on the excitability of glutamatergic and GABAergic neurons in the developing RSC, and suggest that positive allosteric modulators of these receptors could ameliorate ethanol intoxication-induced neurodegeneration during late stages of fetal development.

Comparison between Intravenous Magnesium and Lidocaine Administration on Postoperative Pain during Spinal Anesthesia for Anal Surgery

Background: Perioperative analgesia has been administered traditionally as opioid analgesics, but routine use of opioids for postoperative analgesia has recently been critically challenged. Excessive use of potent opioids may actually increase postoperative pain as a result of rapid elimination and development of acute tolerance and decrease patient satisfaction. Objective: The aim of this study was to assess and compare the effect of IV infusion of lidocaine and magnesium sulphate (Mg) as adjuvant for postoperative pain in anal surgery after spinal anesthesia regarding duration, potency of analgesia, analgesic consumption and hemodynamics. Patients and methods: In this prospective, observational, randomized, double blinded (nurse and junior doctor) placebo study, 150 patients of ASA (American Society of Anesthesiologists) physical status I and II with the age between 18-40 year, undergoing anal surgery under spinal anesthesia were included. The study was conducted in Al-Azhar University Hospital, Assiut during the period from June 2018 to Oct 2018. Results: The results showed that there were significant differences between the three groups according to BP and HR. The patients in Mg group showed more hypotension and bradycardia than the patients in lidocaine and placebo groups. Patients in Mg group showed lower VAS score than lidocaine and placebo groups. The amount of analgesic consumption was lower in Mg group than lidocaine and placebo groups. Conclusion: Usage of IV MgSO4 at 50 mg/kg followed by continuous infusion of 10 mg/kg/h leading to decrease in postoperative pain and analgesic consumption in patients undergoing anal surgery under spinal anesthesia.

Involvement of metabotropic glutamate receptor 5 in ethanol regulation of NMDA receptor activity in rat substantia gelatinosa neurons

AimsGlutamatergic receptors are important targets of ethanol. Intake of ethanol may produce analgesic effects. The present study examined the effects of ethanol on the activity of ionotropic glutamate receptors in spinal cord substantia gelatinosa (SG) neurons, critical neurons involved in nociceptive transmission. Main methodsWhole-cell recordings were made from SG neurons of the lumbar spinal cord slices from 15 to 20-day-old rats. Ethanol and glutamate receptor agonists or antagonists were applied by superfusion. Key findingEthanol (50 and 100 mM) applied by superfusion for 5 min dose-dependently decreased the amplitude of evoked excitatory postsynaptic potential in SG neurons. Superfusion of ethanol (100 mM) for 15 min consistently inhibited NMDA- or AMPA-induced depolarizations in SG neurons. Ethanol (100 mM) also inhibited the depolarizations induced by glutamate. However, ethanol inhibition of glutamate-induced responses significantly decreased at 10–15 min following continuous superfusion, suggesting the development of acute tolerance to the inhibition during prolonged exposure. Application of MPEP hydrochloride (an antagonist of metabotropic glutamate receptor [mGluR] 5) or GF109203X (a protein kinase C [PKC] inhibitor), together with ethanol significantly blocked the tolerance. The inhibition by ethanol of the NMDA-induced, but not AMPA-induced, depolarizations significantly decreased at 15 min during continuous superfusion while ACPD (a mGluR agonist) was co-applied with ethanol. SignificanceThe results suggest that (1) ethanol exposure may inhibit ionotropic glutamate receptor-mediated neurotransmission; (2) regulation of NMDA receptor function by mGluR5/PKC pathways may be involved in the development of the tolerance to ethanol inhibition of glutamate-induced responses during prolonged exposure in SG neurons.

AMPA receptor positive allosteric modulators attenuate morphine tolerance and dependence

Development of opioid tolerance and dependence hinders the use of opioids for the treatment of chronic pain. In searching for the mechanism and potential intervention for opioid tolerance and dependence, we studied the action of two positive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR PAMs). In mice treated with morphine (100 mg/kg, s.c.), acute morphine tolerance and dependence developed in 4–6 h. Treatment with aniracetam, a well-established AMPAR PAM, was able to completely prevent and reverse the development of acute antinociceptive tolerance to morphine. Partial, but significant, effects of aniracetam on acute morphine induced-physical dependence were also observed. Moreover, aniracetam significantly reversed the established morphine tolerance and dependence in a chronic model of morphine tolerance and dependence produced by intermittent morphine (10 mg/kg, s.c. for 5d). In addition, HJC0122, a new AMPAR PAM was found to have similar effects as aniracetam but with a higher potency. These previously undisclosed actions of AMPAR PAMs are intriguing and may shed lights on understanding the APMA signaling pathway in opioid addiction. Moreover, these data suggest that AMPAR PAMs may have utility in preventing and treating morphine tolerance and dependence.

Differential development of acute tolerance may explain heightened rates of impaired driving after consumption of alcohol mixed with energy drinks versus alcohol alone.

Consumers of alcohol mixed with energy drinks (AmED) are more likely to drive while impaired when compared to alcohol alone consumers. In addition, acute tolerance to the internal cues of feelings of intoxication is known to contribute to maladaptive decisions to drive while impaired. Therefore, the purpose of this study was to determine whether there is differential development of acute tolerance for AmED versus alcohol alone for ratings of willingness to drive after alcohol consumption. Social drinkers (n = 12) attended 4 separate sessions where they received alcohol and energy drinks, alone and in combination. The development of acute tolerance to alcohol was assessed for several objective (a computerized cued go/no-go reaction time task) and subjective measures at matched breath alcohol concentrations (BrACs) for the ascending and descending limbs of the BrAC curve. The results indicated that alcohol administration decreased willingness to drive ratings. Acute tolerance was observed in the AmED dose condition for only the willingness to drive ratings that were significantly higher on the descending versus ascending test. Alcohol-induced impairments of the computer task performance did not exhibit any acute tolerance. Therefore, the differential development of acute tolerance may explain why many studies observe higher rates of impaired driving for AmED consumers compared to alcohol alone consumers. Because drunk driving is a major public health concern, alcohol consumers should be warned that the use of energy drink mixers with alcohol could lead to a false sense of security in one's ability to drive after drinking. (PsycINFO Database Record

GCY-35/GCY-36\u2014TAX-2/TAX-4 Signalling in O2 Sensory Neurons Mediates Acute Functional Ethanol Tolerance in Caenorhabditis elegans

Ethanol is a widely used beverage and abused drug. Alcoholism causes severe damage to human health and creates serious social problems. Understanding the mechanisms underlying ethanol actions is important for the development of effective therapies. Alcohol has a wide spectrum of effects on physiological activities and behaviours, from sensitization to sedation and even intoxication with increasing concentrations. Animals develop tolerance to ethanol. However, the underlying mechanisms are not well understood. In Caenorhabditis elegans, NPR-1 negatively regulates the development of acute tolerance to ethanol. Here, using in vivo Ca2+ imaging, behavioural tests and chemogenetic manipulation, we show that the soluble guanylate cyclase complex GCY-35/GCY-36—TAX-2/TAX-4 signalling pathway in O2 sensory neurons positively regulates acute functional tolerance in npr-1 worms.

Opioid-induced hyperalgesia in clinical anesthesia practice: what has remained from theoretical concepts and experimental studies?

This article reviews the phenomenon of opioid-induced hyperalgesia (OIH) and its implications for clinical anesthesia. The goal of this review is to give an update on perioperative prevention and treatment strategies, based on findings in preclinical and clinical research. Several systems have been suggested to be involved in the pathophysiology of OIH with a focus on the glutaminergic system. Very recently preclinical data revealed that peripheral μ-opioid receptors (MORs) are key players in the development of OIH and acute opioid tolerance (AOT). Peripheral MOR antagonists could, thus, become a new prevention/treatment option of OIH in the perioperative setting. Although the impact of OIH on postoperative pain seems to be moderate, recent evidence suggests that increased hyperalgesia following opioid treatment correlates with the risk of developing persistent pain after surgery. In clinical practice, distinction among OIH, AOT and acute opioid withdrawal remains difficult, especially because a specific quantitative sensory test to diagnose OIH has not been validated yet. Since the immediate postoperative period is not ideal to initiate long-term treatment for OIH, the best strategy is to prevent its occurrence. A multimodal approach, including choice of opioid, dose limitations and addition of nonopioid analgesics, is recommended.

Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.

Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue. We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C.elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C.elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc). We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.

Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia.

BackgroundThe development of antinociceptive tolerance following repetitive administration of opioid analgesics significantly hinders their clinical use. Evidence has accumulated indicating that microglia within the spinal cord plays a critical role in morphine tolerance. The inhibitor of microglia is effective to attenuate the tolerance; however, the mechanism is not fully understood. Our present study investigated the effects and possible mechanism of a natural product procyanidins in improving morphine tolerance via its specific inhibition on NOD-like receptor protein3 (NLRP3) inflammasome in microglia.MethodsCD-1 mice were used for tail-flick test to evaluate the degree of pain. The microglial cell line BV-2 was used to investigate the effects and the mechanism of procyanidins. Reactive oxygen species (ROS) produced from BV-2 cells was evaluated by flow cytometry. Cell signaling was measured by western blot assay and immunofluorescence assay.ResultsCo-administration of procyanidins with morphine potentiated its antinociception effect and attenuated the development of acute and chronic morphine tolerance. Procyanidins also inhibited morphine-induced increase of interleukin-1β and activation of NOD-like receptor protein3 (NLRP3) inflammasome. Furthermore, procyanidins decreased the phosphorylation of p38 mitogen-activated protein kinase, inhibited the translocation of nuclear factor-κB (NF-κB), and suppressed the level of reactive oxygen species in microglia.ConclusionsProcyanidins suppresses morphine-induced activation of NLRP3 inflammasome and inflammatory responses in microglia, and thus resulting in significant attenuation of morphine antinociceptive tolerance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0520-z) contains supplementary material, which is available to authorized users.

Perioperative opioids aggravate obstructive breathing in sleep apnea syndrome: mechanisms and alternative anesthesia strategies.

Opioids induce and increase the severity of most sleep-disordered breathing in all patients, but especially in morbidly obese patients. Discussed herein are the direct impact and mechanisms of opioids on inducing and exacerbating obstructive sleep apnea syndrome in normal and morbidly obese patients. Respiratory depression is a larger problem than obstructive sleep apnea syndrome during the first night after an opioid anesthesia because of the reduced amount of deep sleep and rapid-eye-movement sleep. Acute tolerance to the analgesic effects of opioids can be observed after one anesthetic opioid dose, although tolerance to the side-effects of opioids develops more slowly. Therefore, it makes sense to avoid all opioids intraoperatively. A recently developed multimodal nonopioid anesthesia method may prevent development of acute tolerance and facilitate postoperative pain management with less opioids and sleep-disordered breathing. A multimodal nonopioid anesthesia method avoids the necessity for intraoperative opioids, reduces the need for postoperative opioid use, and improves analgesia with less narcotic.

FOC8-3COMPARISON OF EXTRACTS FROM ROOT OFRHODIOLA ROSEA AND RHODIOLA KIRILOWIIINHIBITORY ACTION ON ALCOHOL TOLERANCE DEVELOPMENT IN RATS

The aim of this study was to examine the ability of extracts from root of Rhodiola rosea (RR) and Rhodiola kirilowii (RK) to inhibit the development of acute ethanol tolerance. The ethanol-water (1:1) extracts were standardized on phenylpropanoids (rosavin, rosin, rosarin) and phenylethanoids (salidroside, p-tyrosol) contents. The experiments were performed …

A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery.

Tolerance to remifentanil during sevoflurane anesthesia may increase postoperative analgesic requirements. Low-dose naloxone not only has been shown to block the development of acute opioid tolerance but also to ameliorate undesired opioid-induced side effects. We hypothesized that naloxone prevents the acute opioid tolerance produced by a large dose of remifentanil, and reduces the incidence of opioid-induced side effects. Seventy-two patients undergoing open colorectal surgery were randomly assigned to receive intraoperative remifentanil (1) small dose at 0.1 μg/kg/min; (2) large dose at 0.30 μg/kg/min; or (3) large dose at 0.30 μg/kg/min combined with low-dose naloxone at 0.25 μg/kg/h just after the induction. Cumulative morphine consumption, postoperative pain scores, incidence of opioid-related side effects, time to recovery of bowel function, and length of hospital stay were recorded. Cumulative morphine consumption at 24 h after surgery was higher in the large-dose remifentanil group (28 ± 12 mg) compared with the small-dose remifentanil group (17 ± 12 mg), and large-dose remifentanil-naloxone group (18 ± 9 mg), (P < 0.001). The median time to return of bowel function was shorter in the large-dose remifentanil-naloxone group than the other two groups (P < 0.05). The median length of hospital stay was lower in the large-dose remifentanil-naloxone group (8 [interquartile range: 8-12] days) compared with the small-dose remifentanil group (12 [interquartile range: 9-15] days) and large-dose remifentanil group (12 [interquartile range: 10-13] days), (P < 0.001). Naloxone infusion prevented the acute opioid tolerance, provided a quicker recovery of bowel function, and reduced the length of hospital stay after open colorectal surgery.

An Assay for Measuring the Effects of Ethanol on the Locomotion Speed of Caenorhabditis elegans.

Alcohol use disorders are a significant public health concern, for which there are few effective treatment strategies. One difficulty that has delayed the development of more effective treatments is the relative lack of understanding of the molecular underpinnings of the effects of ethanol on behavior. The nematode, Caenorhabditis elegans (C. elegans), provides a useful model in which to generate and test hypotheses about the molecular effects of ethanol. Here, we describe an assay that has been developed and used to examine the roles of particular genes and environmental factors in behavioral responses to ethanol, in which locomotion is the behavioral output. Ethanol dose-dependently causes an acute depression of crawling on an agar surface. The effects are dynamic; animals exposed to a high concentration demonstrate an initial strong depression of crawling, referred to here as initial sensitivity, and then partially recover locomotion speed despite the continued presence of the drug. This ethanol-induced behavioral plasticity is referred to here as the development of acute functional tolerance. This assay has been used to demonstrate that these two phenotypes are distinct and genetically separable. The straightforward locomotion assay described here is suitable for examining the effects of both genetic and environmental manipulations on these acute behavioral responses to ethanol in C. elegans.