Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity.

The neural balance between facilitation and inhibition determines the final tendency of central sensitization. Nerve injury-induced hypersensitivity was considered as the results from the enhanced ascending facilitation and the diminished descending inhibition. The role of dopaminergic transmission in the descending inhibition has been well documented, but its underlying molecular mechanisms are unclear. Previous studies demonstrated that the lysine dimethyltransferase G9a/G9a-like protein (Glp) complex plays a critical role in cocaine-induced central plasticity, and given cocaine's role in the nerve system is relied on its function on dopamine system, we herein proposed that the reduced inhibition of dopaminergic transmission was from the downregulation of tyrosine hydroxylase expression by G9a/Glp complex through methylating its gene Th After approval by the Animal Care and Use Committee, C57BL/6 mice were used for pain behavior using von Frey after spared nerve injury, and Th CpG islands methylation was measured using bisulfite sequencing at different nerve areas. The inhibitor of G9a/Glp, BIX 01294, was administered intraventricularly daily with bolus injection. The protein levels of G9a, Glp, and tyrosine hydroxylase were measured with immunoblotting. Dopamine levels were detected using high-performance liquid chromatography. The expression of G9a but not Glp was upregulated in ventral tegmental area at post-injury day 4 till day 49 (the last day of the behavioral test). Correspondingly, the Th CpG methylation is increased, but the tyrosine hydroxylase expression was downregulated and the dopamine level was decreased. After the intracerebroventriclar injection of BIX 01294 since the post-injury days 7 and 14 for consecutive three days, three weeks, and six weeks, the expression of tyrosine hydroxylase was upregulated with a significant decrease in Th methylation and increase in dopamine level. Moreover, the pain after G9a/Glp inhibitor was attenuated significantly. In sum, methytransferase G9a/Glp complex partially controls dopaminergic transmission by methylating Th in peripheral nerve injury-induced neuropathic pain.

Oxytocin ameliorates cognitive impairments by attenuating excitation/inhibition imbalance of neurotransmitters acting on parvalbumin interneurons in a mouse model of sepsis-associated encephalopathy.

Inflammation plays a crucial role in the initiation and progression of sepsis, and it also induces alterations in brain neurotransmission, thereby contributing to the development of sepsis-associated encephalopathy (SAE). Parvalbumin (PV) interneurons are pivotal contributors to cognitive processes in various central dysfunctions including SAE. Oxytocin, known for its ability to augment the firing rate of gamma-aminobutyric acid (GABA)ergic interneurons and directly stimulate inhibitory interneurons to enhance the tonic inhibition of pyramidal neurons, has prompted an investigation into its potential effects on cognitive dysfunction in SAE. In the current study, we administered intranasal oxytocin to the SAE mice induced by lipopolysaccharide (LPS). Behavioral assessments, including open field, Y-maze, and fear conditioning, were used to evaluate cognitive performance. Golgi staining revealed hippocampal synaptic deterioration, local field potential recordings showed weakened gamma oscillations, and immunofluorescence analysis demonstrated decreased PV expression in the cornu ammonis 1 (CA1) region of the hippocampus following LPS treatment, which was alleviated by oxytocin. Furthermore, immunofluorescence staining of PV co-localization with vesicular glutamate transporter 1 or vesicular GABA transporter indicated a balanced excitation/inhibition effect of neurotransmitters on PV interneurons after oxytocin administration in the SAE mice, leading to improved cognitive function. In conclusion, cognitive function improved after oxytocin treatment. The number of PV neurons in the hippocampal CA1 region and the balance of excitatory/inhibitory synaptic transmission on PV interneurons, as well as changes in local field potential gamma oscillations in the hippocampal CA1 region, may represent its specific mechanisms.

Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial.

OBJECTIVE: To determine whether a single low dose of esketamine administered after childbirth reduces postpartum depression in mothers with prenatal depression. DESIGN: Randomised, double blind, placebo controlled trial with two parallel arms. SETTING: Five tertiary care hospitals in China, 19 June 2020 to 3 August 2022. PARTICIPANTS: 364 mothers aged ≥18 years who had at least mild prenatal depression as indicated by Edinburgh postnatal depression scale scores of ≥10 (range 0-30, with higher scores indicating worse depression) and who were admitted to hospital for delivery. INTERVENTIONS: Participants were randomly assigned 1:1 to receive either 0.2 mg/kg esketamine or placebo infused intravenously over 40 minutes after childbirth once the umbilical cord had been clamped. MAIN OUTCOME MEASURES: The primary outcome was prevalence of a major depressive episode at 42 days post partum, diagnosed using the mini-international neuropsychiatric interview. Secondary outcomes included the Edinburgh postnatal depression scale score at seven and 42 days post partum and the 17 item Hamilton depression rating scale score at 42 days post partum (range 0-52, with higher scores indicating worse depression). Adverse events were monitored until 24 hours after childbirth. RESULTS: A total of 364 mothers (mean age 31.8 (standard deviation 4.1) years) were enrolled and randomised. At 42 days post partum, a major depressive episode was observed in 6.7% (12/180) of participants in the esketamine group compared with 25.4% (46/181) in the placebo group (relative risk 0.26, 95% confidence interval (CI) 0.14 to 0.48; P<0.001). Edinburgh postnatal depression scale scores were lower in the esketamine group at seven days (median difference -3, 95% CI -4 to -2; P<0.001) and 42 days (-3, -4 to -2; P<0.001). Hamilton depression rating scale scores at 42 days post partum were also lower in the esketamine group (-4, -6 to -3; P<0.001). The overall incidence of neuropsychiatric adverse events was higher in the esketamine group (45.1% (82/182) v 22.0% (40/182); P<0.001); however, symptoms lasted less than a day and none required drug treatment. CONCLUSIONS: For mothers with prenatal depression, a single low dose of esketamine after childbirth decreases major depressive episodes at 42 days post partum by about three quarters. Neuropsychiatric symptoms were more frequent but transient and did not require drug intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04414943.

Early postoperative cognitive dysfunction is associated with higher cortisol levels in aged patients following hip fracture surgery.

This study aimed to evaluate the relationship between plasma cortisol levels and the occurrence of postoperative cognitive dysfunction (POCD) in aged patients following hip fracture surgery. A total of 175 patients, aged 65 years or older, who were scheduled for hip fracture surgery with spinal anesthesia were enrolled. Perioperative plasma levels of cortisol and neurocognitive tests were determined at 1 day preoperatively and 7 days postoperatively. Seventy-seven patients completed both blood sample collections and neurocognitive tests. POCD occurred in 29.9 % of patients at 7 days postoperatively. POCD patients presented significantly higher cortisol levels compared with non-POCD patients (P < 0.05). Furthermore, plasma cortisol levels were negatively correlated with mini-mental state examination (MMSE) scores at 7 days postoperatively (P < 0.0001). A specificity of 93 % and a sensitivity of 35 % were identified for the plasma cortisol measurement to discriminate POCD patients from non-POCD patients. The results suggest higher plasma cortisol levels are associated with POCD in aged patients following hip fracture surgery with spinal anesthesia.

Opioid Free Total Intravenous Anesthesia With Dexmedetomidine-Esketamine-Lidocaine for Patients Undergoing Lumpectomy.

Background: The aim of the study was to evaluate the feasibility of the opioid-free anesthesia (OFA) technique with dexmedetomidine, esketamine, and lidocaine among patients diagnosed with benign breast mass and scheduled for lumpectomy. Methods: We enrolled 80 female patients who were aged from 18 to 60 years, graded with American Society of Anesthesiologists physical status I or II, diagnosed with benign breast mass, and scheduled for lumpectomy. These patients were randomly treated with OFA or opioid-based anesthesia (OBA). Dexmedetomidine-esketamine-lidocaine and sufentanil-remifentanil were administered in OFA and OBA group, respectively. We mainly compared the analgesic efficacy of OFA and OBA technique, as well as intraoperative hemodynamics, the quality of recovery, and satisfaction score of patients. Results: There was no significant difference between the two groups with regard to visual analogue scale (VAS) score at 2, 12, and 24 h after extubation. However, the time to first rescue analgesic was prolonged in OFA group than that in OFB group (6.18 ± 1.00 min vs. 7.40 ± 0.92 min, P = 0.000). Further, mean arterial pressure and heart rate at T0 (entering operating room), T1 (before anesthesia induction), T2 (immediately after intubation), T3, T4, and T5 (1, 5, and 10 min after surgical incision, respectively) were significantly higher in OFA group than that in OBA group. Incidence of hypotension and bradycardia was lower in OFA group. Consistently, fewer patients in OFA group consumed atropine (8% vs. 32%, P = 0.019) and ephedrine (5% vs. 38%, P = 0.001) compared to OBA group. Furthermore, patients in OFA group had a longer awakening time (7.14 ± 2.63 min vs. 4.54 ± 1.14 min, P = 0.000) and recovery time of orientation (11.76 ± 3.15 min vs. 6.92 ± 1.19 min, P = 0.000). Fewer patients in the OFA group experienced postoperative nausea and vomiting (PONV) (11% vs. 51%, P = 0.000) and consumed ondansetron (5% vs. 35%, P = 0.003) compared to OBA group. And patients in OFA group had a higher satisfaction score than those in OBA group (9 (8 - 9) vs. 7 (7 - 8), P = 0.000). Conclusion: For patients undergoing lumpectomy, OFA technique with dexmedetomidine-esketamine-lidocaine showed a better postoperative analgesic efficacy, a more stable hemodynamics, and a lower incidence of PONV. However, such advantage of OFA technique should be weighed against a longer awakening time and recovery time of orientation in clinical practice.

Deficit of perineuronal net induced by maternal immune activation mediates the cognitive impairment in offspring during adolescence.

Maternal immune activation (MIA) during pregnancy is considered a risk factor for neurodevelopment in the offspring, resulting in behavioral abnormalities. Furthermore, adolescence is a vulnerable period for developing different psycho-cognitive deficits. Here, we aimed to observe the cognitive consequences of prenatal MIA exposure in adolescents and explored the underlying mechanisms. We divided dams into CON and MIA groups after inducing a mouse model of MIA using lipopolysaccharide (120 µg/kg) on gestational day 15. Open field (OF), elevated plus maze (EPM), and novel object recognition (NOR) tests were performed on postnatal day (PD) 35-37. The expression of hippocampal Wisteria floribunda agglutinin (WFA)+ perineuronal net (PNN), parvalbumin (PV), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule-1(Iba-1) were evaluated using immunofluorescence, and the expression of matrix metalloprotein-9 (MMP-9) in the hippocampus was assessed using the western blot. Following the infusion of chondroitinase ABC (ChABC) into CA1 in the offspring from the CON group on PD 30, they were divided into ChABC and Sham groups. OF, EPM, and NOR were performed on PD 35-37. Compared to the CON group, decreased exploration time of the novel object and preference ratio were observed in the MIA group. Meanwhile, the MIA group presented significantly decreased WFA+ PNN in CA1, increased Iba-1+ microglia, and MMP-9 in the hippocampus. Additionally, the density of PV+ neurons and GFAP+ astrocytes was comparable between both groups. After digesting the PNN, the exploration time of novel object and preference ratio decreased in the ChABC group compared to the Sham group. Conclusively, the PNN deficit in CA1 caused by prenatal MIA might, at least partially, induce cognitive impairment in adolescents. Microglia and MMP-9 may also be potential candidates for PNN deficit after MIA.

Hyperthyroidism patients have shorter onset and duration time of rocuronium than euthyroidism patients.

PURPOSE: The possibility of altered response to nondepolarizing muscle relaxants in hyperthyroidism patients has not been documented. The present study was conducted to observe the onset and duration of rocuronium induced neuromuscular blockade in hyperthyroidism patients. METHODS: Eighteen hyperthyroidism patients undergoing subtotal thyroidectomy (H group) and eighteen euthyroidism patients undergoing operation on neck (E group) were studied. Anesthetized with propofol and fentanyl, all patients received rocuronium 0.6 mg/kg. The twitch high of adductor pollicis muscle was monitored by acceleromyography. The onset, the duration of the initial dose, the durations of the repeated maintenance doses, the repeated times, and the total doses of rocuronium were observed. RESULTS: The onset time of rocuronium in H group was significantly shorter than that in E group (P<0.05). The duration of the initial dose as well as the durations of the repeated maintenance doses in H group was significantly shorter than that in E group (P<0.05). The repeated times and the total dosage of rocuronium in H group were significantly more than that in E group (P<0.05). CONCLUSIONS: Hyperthyroidism patients experience a shorter onset time, a shorter duration, and require larger doses of rocuronium than euthyroidism patients.

Environmental conditions differentially affect neurobehavioral outcomes in a mouse model of sepsis-associated encephalopathy.

Brain dysfunction remains a common complication after sepsis development and is an independent risk factor for a poorer prognosis and an increased mortality. Here we tested the hypothesis that the behavioral outcomes after lipopolysaccharides (LPS) administration are exacerbated by an impoverished environment (IE) and alleviated by an enriched environment (EE), respectively. Mice were randomly allocated in a standard environment (SE), an EE, or an IE for 4 weeks after LPS or normal saline (NS) administration. Neurobehavioral alternations were assessed by the open field, novel objective recognition, and fear conditioning tests. The expressions of proinflammatory cytokines (tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-10), ionized calcium-binding adaptor molecule-1 (IBA1)-positive cells as well as glial fibrillary acidic protein (GFAP)-positive cells, brain derived neurotrophic factor (BDNF), 5-bromo-2-deoxyuridine-labeled cells in the dentate gyrus of the hippocampus, and the number of dendritic spines in the hippocampal CA1 were determined. Our results showed that the some of the neurocognitive abnormalities induced by LPS administration can be aggravated by stressful conditions such as IE but alleviated by EE. These neurocognitive alternations were accompanied by significant changes in biomarkers of immune response and hippocampal synaptic plasticity. In summary, our study confirmed the negative impact of IE and the positive effects of EE on the cognitive function after LPS administration, with potential implications to the basis of sepsis-related cognitive impairments in the critically ill patients.

Comparison Between the Use of Ropivacaine Alone and Ropivacaine With Sufentanil in Epidural Labor Analgesia.

To compare the analgesic efficacy and safety of the sole local anesthetic ropivacaine with the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil given epidurally on the labor pain control.After institutional review board approval and patient consent, a total of 500 nulliparas requesting epidural labor analgesia were enrolled and 481 eventually were randomized into 2 groups: a sole local anesthetic group (ropivacaine 0.125%) and a combination of local anesthetic and opioidergic analgesic group (0.125% ropivacaine + 0.3 µg/mL sufentanil). After the test dose, a 10-mL epidural analgesic solution was given in a single bolus, followed by intermittent bolus injection of 10 to 15 mL of the solution. The primary outcome was the analgesic efficacy measured using Numerical Rating Scale (NRS) of pain. Other maternal and infant variables were evaluated as secondary outcomes.A total of 346 participants completed the study. The median NRS pain score during the 1st stage of labor was significantly lower in the combination group 2.2 (interquartile range [IQR]: 1.8-2.7) comparing to the sole local analgesic group 2.4 (IQR: 2.0-2.8) (P < 0.0001). No significant difference was observed in NRS pain score prior epidural analgesia and during the 2nd stage of labor. Patients in both groups rated same satisfaction of analgesia. Patients in the sole local analgesic group experienced fewer side effects than those in the combination group (37.7% vs 47.2%, P = 0.082). The individual analgesia-related cost in the sole local analgesic group was less ($5.7 ±â€Š2.06) than that in the combination group ($9.76 ±â€Š3.54) (P < 0.0001). The incidence of 1-minute Apgar ≤ 7 was lower in the sole local analgesic group 2 (1.2%) than the combination group 10 (5.5%) (P = 0.038). No difference was found between other secondary outcomes.The sole local anesthetic ropivacaine produces a comparable labor analgesic effect as the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil at different stages of labor (ΔNRS = 0.2) but the former has less side effects, lower cost, and less incidence of lower 1-minute Apgar scoring. These results imply the necessity of a systematic reevaluation of epidural labor analgesia with sole local anesthetics against combination regimens of local anesthetics and other opioids.

Modeled behavior of neuropathic pain with social defect in rats: a preliminary methodology evaluation.

BACKGROUND: Social defect and chronic pain are 2 major health problems and recent data has demonstrated that they generally exist concurrently. However, a powerful evaluation model on the behavioral change is lacking. This study was designed to evaluate the behavioral curves using a statistically modeled trajectory analysis in neuropathic animals with or without social defect exposure. MATERIAL/METHODS: After approval by the institutional animal care committee, Sprague-Dawley rats were randomized into different interventional groups with 15 animals each. Sprague-Dawley rats underwent spared nerve injury (SNI) to establish the neuropathic pain model, of which the mechanical withdrawal threshold was measured using von Frey filaments for a period of 105 days. Otherwise, a modified version of the resident (Long-Evans rats)-intruder paradigm was applied to produce a social defect animal model through the elevated plus maze (EPM). After raw data collection, we modeled them into a powerful statistical effects analysis to build up the behavioral change tendency in single SNI or in combined SNI and social defect animals. RESULTS: The random and fixed effects analyses of the pain behavior after SNI were successfully modeled and demonstrated a gradient recovery tendency during the 15-week post-injury observational period. Correspondingly, SNI rats exhibited increased social defected symptoms, as indicated by the increased anxiety-like behavior in the EPM test. In addition, continuous social defect stress for 5 days or 10 days, respectively, partially attenuated and exacerbated SNI-induced allodynia in both random and fixed effects models. Five days but not 10 days social defect ameliorated SNI-associated anxiety-like behavior. CONCLUSIONS: These data suggest that statistically powerful analysis of nerve injury-induced neuropathic pain is a highly sensitive model to determine the behavioral change tendency and distinguish them among behavior curves with or without social defect, and the combination of SNI with resident-intruder paradigm may be a suitable model for behavior evaluation of neuropathic pain with social defect.

Minocycline improves postoperative cognitive impairment in aged mice by inhibiting astrocytic activation.

Astrocytes are proving to be critical for the development of cognitive functions. In addition, astrocytic activation contributes to cognitive impairment induced by chronic cerebral hypoperfusion. Minocycline has been shown to exhibit long-term neuroprotective effects in vascular cognitive impairment rat models through the inhibition of astrogliosis, and has demonstrated potential for the prevention and treatment of postoperative cognitive decline in elderly patients. This study aimed to examine the effect of minocycline on hippocampal astrocytes and long-term postoperative cognitive dysfunction in aged mice. Mice were intraperitoneally injected with 45 mg/kg minocycline once a day for 30 days after 70% hepatectomy. Hippocampus-dependent spatial memory ability was evaluated using the Morris water maze test. The expression levels of hippocampal glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 were evaluated by western blotting, and the hippocampal mRNA relative expression levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 were tested using real-time PCR. The Morris water maze test showed that escape latency and swim distance were significantly prolonged by the surgery, but the extent of impairment was mitigated by minocycline treatment. Hippocampal GFAP levels and mRNA levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 showed corresponding changes that were consistent with the variations in spatial memory. Minocycline was able to alleviate hepatectomy-related long-term spatial memory impairment in aged mice, and was associated with reduced levels of hippocampal GFAP and proinflammatory cytokines resulting from astrocytic activation.

Regular intermittent bolus provides similar incidence of maternal fever compared with continuous infusion during epidural labor analgesia.

OBJECTIVES: To compare the effects of regular intermittent bolus versus continuous infusion for epidural labor analgesia on maternal temperature and serum interleukin-6 (IL-6) level. METHODS: This randomized trial was performed in Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu Province, China between October 2012 and February 2014. Either regular intermittent bolus (RIB, n=66) or continuous infusion (CI, n=66) was used for epidural labor analgesia. A bolus dose (10 ml of 0.08% ropivacaine + 0.4 ug·ml-1 sufentanil) was manually administrated once an hour in the RIB group, whereas the same solution was continuously infused at a constant rate of 10 ml·h-1 in the CI group. Maternal tympanic temperature and serum IL-6 level were measured hourly from baseline to one hour post partum. The incidences of fever (>/=38 degree celsius ) were calculated. RESULTS: The incidence of maternal fever was similar between the 2 groups. There was a rising trend in mean temperature over time in both groups, but no statistical difference was detected between the groups at respective time points; maternal serum IL-6 showed similar changes. CONCLUSION: Compared with continuous infusion, regular intermittent bolus presents with the same incidence of maternal fever for epidural labor analgesia. Interleukin-6 elevation could be involved in mean maternal temperature increase.