Continuous quality improvement: reducing informed consent form signing errors.

BACKGROUND: Adherence to ethical guidelines and regulations and protecting and respecting the dignity and autonomy of participants by obtaining a valid informed consent form (ICF) prior to participation in research are crucial; The subjects did not add signatures next to the corrections made to signatures or dates on the ICF, Multiple signatures in other fields, ICF missing/missing signature, Incorrect ICF version Signed after modification, Correction tape used to correct signature, Impersonated signature, Non-research-member signature, however, ICFs are often not properly completed, which must be addressed. This study analyzed ICF signing errors and implemented measures to reduce or prevent these errors. METHODS: We used the plan-do-check-act (PDCA) cycle to help improve the correctness and validity of ICF signing. RESULTS: Interim and final reports from January 2016 to February 2020 including 363 ICFs were studied. The total proportion of correct ICF signatures (200, 83.3%) following the PDCA intervention was significantly higher than that before the intervention (P < 0.05). Analysis of the types of signing error demonstrated that signature errors were significantly reduced after the intervention, particularly for subjects did not add signatures next to the corrections made to signatures or dates on the ICF (16, 6.7%) and impersonated signature (0; P < 0.05). CONCLUSIONS: The proportions of other error types-multiple signatures in other fields, missing or unsigned ICF, incorrect signature order, incorrect ICF version, use of correction tape to correct signature, and non-medical profession members signing the ICF-did not differ significantly.

Sugammadex reversal of muscle relaxant blockade provided less Post-Anesthesia Care Unit adverse effects than neostigmine/glycopyrrolate.

Sugammadex is a direct reversal agent of aminosteroid muscle relaxants, particularly rocuronium, with promptly and completely reverse of deep neuromuscular block (NMB), which allows better surgical conditions. Sugammadex exhibits advantages over indirect reversal agent acetylcholinesterase inhibitor neostigmine with less adverse effects. In this retrospective review, we compared the incidence of postoperative vomiting (POV), postoperative urinary retention (POUR), and hemodynamic changes between sugammadex and neostigmine/glycopyrrolate in reversal of muscular blockade. Sugammadex showed superior in all three aspects. The heart rate was 7.253 lower (P < 0.0001) and mean arterial pressure was 5.213 lower (P < 0.0001) in sugammadex group. The POV of neostigmine/glycopyrrolate group was 3.16 times more than sugammadex group (OR = 3.16, p < 0.0001), and POUR of neostigmine/glycopyrrolate group was 4.291 times more than sugammadex group (OR = 4.291, p < 0.0001). Sugammadex showed better hemodynamic stability, and lower incidence of POV and POUR than neostigmine/glycopyrrolate.

Detection and Evaluation of Serological Biomarkers to Predict Osteoarthritis in Anterior Cruciate Ligament Transection Combined Medial Meniscectomy Rat Model.

Biomarkers are essential tools in osteoarthritis (OA) research, clinical trials, and drug development. Detecting and evaluating biomarkers in OA research can open new avenues for researching and developing new therapeutics. In the present report, we have explored the serological detection of various osteoarthritis-related biomarkers in the preclinical model of OA. In this surgical OA model, we disrupted the medial tibial cartilage's integrity via anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) of a single joint of Wistar rats. The progression of OA was verified, as shown by the microscopic deterioration of cartilage and the increasing cartilage degeneration scoring from 4 to 12 weeks postsurgery. The concentration of serological biomarkers was measured at two timepoints, along with the complete blood count and bone electrolytes, with biochemical analysis further conducted. The panel evaluated inflammatory biomarkers, bone/cartilage biomarkers, and lipid metabolic pathway biomarkers. In chronic OA rats, we found a significant reduction of total vitamin D3 and C-telopeptide fragments of type II (CTX-II) levels in the serum as compared to sham-operated rats. In contrast, the serological levels of adiponectin, leptin, and matrix metallopeptidase (MMP3) were significantly enhanced in chronic OA rats. The inflammatory markers, blood cell composition, and biochemical profile remained unchanged after surgery. In conclusion, we found that a preclinical model of single-joint OA with significant deterioration of the cartilage can lead to serological changes to the cartilage and metabolic-related biomarkers without alteration of the systemic blood and biochemical profile. Thus, this biomarker profile provides a new tool for diagnostic/therapeutic assessment in OA scientific research.

Scope and Applications of Nanomedicines for the Management of Neuropathic Pain.

Neuropathic pain, resulting from the dysfunction of the peripheral and central nervous system, occurs in a variety of pathological conditions including trauma, diabetes, cancer, HIV, surgery, multiple sclerosis, ischemic attack, alcoholism, spinal cord damage, and many others. Despite the availability of various treatment strategies, the percentage of patients achieving adequate pain relief remains low. The clinical failure of most effective drugs is often not due to a lack of drug efficacy but due to the dose-limiting central nervous system (CNS) toxicity of the drugs that preclude dose escalation. There is a need for cross-disciplinary collaborations to meet these challenges. In this regard, the integration of nanotechnology with neuroscience is one of the most important fields. In recent years, promising preclinical research has been reported in this field. This review highlights the current challenges associated with conventional neuropathic pain treatments, the scope for nanomaterials in delivering drugs across the blood-brain barrier, and the state and prospects of nanomaterials for the management of neuropathic pain.

Propofol-based total intravenous anaesthesia is associated with better survival than desflurane anaesthesia in hepatectomy for hepatocellular carcinoma: a retrospective cohort study.

BACKGROUND: Previous studies have shown that anaesthetic technique can affect outcomes of cancer surgery. We investigated the association between anaesthetic technique and patient outcomes after elective hepatectomy for hepatocellular carcinoma. METHODS: This was a retrospective single-centre cohort study of patients who received elective hepatectomy for hepatocellular carcinoma from January 2005 to December 2014. Patients were grouped according to propofol or desflurane anaesthesia. Kaplan-Meier analysis was performed and survival curves were constructed from the date of surgery to death. After propensity matching, univariable and multivariable Cox regression models were used to compare hazard ratios for death. Subgroup analyses were performed for tumour-node-metastasis staging and distant metastasis and local recurrence. RESULTS: A total of 492 patients (369 deaths, 75.0%) with desflurane anaesthesia and 452 (139 deaths, 30.8%) with propofol anaesthesia were eligible for analysis. After propensity matching, 335 patients remained in each group. In the matched analysis, propofol anaesthesia had a better survival with hazard ratio of 0.47 (95% confidence interval, 0.38-0.59; P<0.001). Subgroup analyses also showed significantly better survival in the absence of distant metastasis (hazard ratio, 0.47; 95% confidence interval, 0.37-0.60; P<0.001) or local recurrence (hazard ratio, 0.22; 95% confidence interval, 0.14-0.34; P<0.001) in the matched groups. CONCLUSIONS: Propofol anaesthesia was associated with better survival in hepatocellular carcinoma patients who underwent hepatectomy. Prospective studies are warranted to evaluate the effects of propofol anaesthesia on surgical outcomes in hepatocellular carcinoma patients.

Melatonin and their analogs as a potential use in the management of Neuropathic pain.

Melatonin (N-acetyl-5-methoxytryptamine), secreted by the pineal gland is known to perform multiple functions including, antioxidant, anti-hypertensive, anti-cancerous, immunomodulatory, sedative and tranquilizing functions. Melatonin is also known to be involved in the regulation of body mass index, control the gastrointestinal system and play an important role in cardioprotection, thermoregulation, and reproduction. Recently, several studies have reported the efficacy of Melatonin in treating various pain syndromes. The current paper reviews the studies on Melatonin and its analogs, particularly in Neuropathic pain. Here, we first briefly summarized research in preclinical studies showing the possible mechanisms through which Melatonin and its analogs induce analgesia in Neuropathic pain. Second, we reviewed research indicating the role of Melatonin in attenuating analgesic tolerance. Finally, we discussed the recent studies that reported novel Melatonin agonists, which were proven to be effective in treating Neuropathic pain.

Magnesium sulfate inhibits binding of lipopolysaccharide to THP-1 cells by reducing expression of cluster of differentiation 14.

We investigated effects of magnesium sulfate (MgSO4) on modulating lipopolysaccharide (LPS)-macrophage binding and cluster of differentiation 14 (CD14) expression. Flow cytometry data revealed that the mean levels of LPS-macrophage binding and membrane-bound CD14 expression (mCD14) in differentiated THP-1 cells (a human monocytic cell line) treated with LPS plus MgSO4 (the LPS + M group) decreased by 28.2% and 25.3% compared with those THP-1 cells treated with LPS only (the LPS group) (P < 0.001 and P = 0.037), indicating that MgSO4 significantly inhibits LPS-macrophage binding and mCD14 expression. Notably, these effects of MgSO4 were counteracted by L-type calcium channel activation. Moreover, the mean level of soluble CD14 (sCD14; proteolytic cleavage product of CD14) in the LPS + M group was 25.6% higher than in the LPS group (P < 0.001), indicating that MgSO4 significantly enhances CD14 proteolytic cleavage. Of note, serine protease inhibition mitigated effects of MgSO4 on both decreasing mCD14 and increasing sCD14. In conclusion, MgSO4 inhibits LPS-macrophage binding through reducing CD14 expression. The mechanisms may involve antagonizing L-type calcium channels and activating serine proteases.

Propofol-based Total Intravenous Anesthesia Is Associated with Better Survival Than Desflurane Anesthesia in Colon Cancer Surgery.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Previous research has shown different effects of anesthetics on cancer cell growth. Here, the authors investigated the association between type of anesthetic and patient survival after elective colon cancer surgery. METHODS: A retrospective cohort study included patients who received elective colon cancer surgery between January 2005 and December 2014. Patients were grouped according to anesthesia received: propofol or desflurane. After exclusion of those who received combined propofol anesthesia with inhalation anesthesia or epidural anesthesia, survival curves were constructed from the date of surgery to death. After propensity matching, univariable and multivariable Cox regression models were used to compare hazard ratios for death. Subgroup analyses were performed for tumor-node-metastasis staging and postoperative metastasis. RESULTS: A total of 706 patients (307 deaths, 43.5%) with desflurane anesthesia and 657 (88 deaths, 13.4%) with propofol anesthesia were eligible for analysis. After propensity matching, 579 patients remained in each group (189 deaths, 32.6%, in the desflurane group vs. 87, 15.0%, in the propofol group). In the matched analyses, the propofol-treated group had a better survival, irrespective of lower tumor-node-metastasis stage (hazard ratio, 0.22; 95% CI, 0.11 to 0.42; P < 0.001) or higher tumor-node-metastasis stage (hazard ratio, 0.42; 95% CI, 0.32 to 0.55; P < 0.001) and presence of metastases (hazard ratio, 0.67; 95% CI, 0.51 to 0.86; P = 0.002) or absence of metastases (hazard ratio, 0.08; 95% CI, 0.01 to 0.62; P = 0.016). Simple propensity score adjustment produced similar findings. CONCLUSIONS: Propofol anesthesia for colon cancer surgery is associated with better survival irrespective of tumor-node-metastasis stage.

Effects of MgSO4 on inhibiting Nod-like receptor protein 3 inflammasome involve decreasing intracellular calcium.

BACKGROUND: Nod-like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex composed of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain. Activation of NLRP3 inflammasome leads to interleukin-1ß (IL-1ß) upregulation and pyroptosis, a proinflammatory cell death characterized by increased cell size. Of note, calcium signaling is crucial for NLRP3 inflammasome activation. This study elucidated the effects of magnesium sulfate (MgSO4), a potent calcium antagonist, on modulating NLRP3 inflammasome. MATERIALS AND METHODS: THP-1 cells, the human monocytic leukemia cell line, were treated with lipopolysaccharide (LPS, 1 µg/ml) plus nigericin (5 µM) (the LPS + Nig group) and LPS plus nigericin plus MgSO4 (20 mM) [the LPS + Nig + M(20)] to facilitate investigations. Levels of IL-1ß, pyroptosis, and NLRP3 inflammasome induction as well as intracellular calcium were assayed. RESULTS: IL-1ß concentration of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.001). Cell size of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P < 0.001). Level of pyroptotic cell death of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.004). NLRP3 mRNA and protein concentrations of the LPS + Nig + M(20) group were also significantly lower than the LPS + Nig group (P = 0.021 and P < 0.001). Similarly, apoptosis-associated speck-like protein containing a caspase recruitment domain speck formation ratio and caspase-1 concentration of the LPS + Nig + M(20) group were significantly lower than the LPS + Nig group (both P < 0.001). The change in intracellular calcium level of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P = 0.001). CONCLUSIONS: MgSO4 inhibits NLRP3 inflammasome, IL-1ß upregulation, and pyroptosis. The mechanism is consistent with decreased intracellular calcium levels.

What information and the extent of information research participants need in informed consent forms: a multi-country survey.

BACKGROUND: The use of lengthy, detailed, and complex informed consent forms (ICFs) is of paramount concern in biomedical research as it may not truly promote the rights and interests of research participants. The extent of information in ICFs has been the subject of debates for decades; however, no clear guidance is given. Thus, the objective of this study was to determine the perspectives of research participants about the type and extent of information they need when they are invited to participate in biomedical research. METHODS: This multi-center, cross-sectional, descriptive survey was conducted at 54 study sites in seven Asia-Pacific countries. A modified Likert-scale questionnaire was used to determine the importance of each element in the ICF among research participants of a biomedical study, with an anchored rating scale from 1 (not important) to 5 (very important). RESULTS: Of the 2484 questionnaires distributed, 2113 (85.1%) were returned. The majority of respondents considered most elements required in the ICF to be 'moderately important' to 'very important' for their decision making (mean score, ranging from 3.58 to 4.47). Major foreseeable risk, direct benefit, and common adverse effects of the intervention were considered to be of most concerned elements in the ICF (mean score = 4.47, 4.47, and 4.45, respectively). CONCLUSIONS: Research participants would like to be informed of the ICF elements required by ethical guidelines and regulations; however, the importance of each element varied, e.g., risk and benefit associated with research participants were considered to be more important than the general nature or technical details of research. Using a participant-oriented approach by providing more details of the participant-interested elements while avoiding unnecessarily lengthy details of other less important elements would enhance the quality of the ICF.

Resveratrol reverses morphine-induced neuroinflammation in morphine-tolerant rats by reversal HDAC1 expression.

BACKGROUND/PURPOSE: We previously showed that subsequent intrathecal (i.t.) injection of resveratrol (30 µg) significantly reverses morphine-evoked neuroinflammation in morphine-tolerant rats. The present study examined the underlying mechanism. METHODS: Male Wistar rats were implanted with two i.t. catheters, one of which was connected to a miniosmotic pump and used for morphine (15 µg/h) or saline infusion for 120 hours. To examine the effects on spinal cord expression of histone deacetylase 1 (HDAC1), the inflammatory cytokine tumor necrosis factor-α (TNF-α), and TNF receptor (TNFR) 1 and TNFR2 during tolerance induction, a tail-flick test was performed prior to infusion and after 24 hours, 48 hours, 72 hours, 96 hours, and 120 hours of infusion. RESULTS: Resveratrol treatment prior to morphine challenge restored the antinociceptive effect of morphine in morphine-tolerant rats and reversed the morphine infusion-induced increase in HDAC1, TNF-α, and TNFR1 expression. Moreover, chronic morphine infusion increased TNFR1-specific expression in neuron in morphine-tolerant rat spinal cords, and this effect was almost completely inhibited by resveratrol treatment prior to morphine challenge. CONCLUSION: Resveratrol restores the antinociceptive effect of morphine by reversing morphine infusion-induced spinal cord neuroinflammation and increase in TNFR1 expression. The reversal of the morphine-induced increase in TNFR1 expression by resveratrol is partially due to reversal of the morphine infusion-induced increase in HDAC1 expression. Resveratrol pretreatment can be used as an adjuvant in clinical pain management for patients who need long-term morphine treatment or with neuropathic pain.

Association between extracellular signal-regulated kinase expression and the anti-allodynic effect in rats with spared nerve injury by applying immediate pulsed radiofrequency.

BACKGROUND: The application of pulsed radiofrequency (PRF) close to the dorsal root ganglia, or peripheral nerves, has been demonstrated to be effective for the treatment of chronic neuropathic pain conditions. The goal of this study was to investigate the analgesic effect of immediate PRF treatment after nerve injury and its possible cellular alterations in the dorsal horn of the spinal cord in rats with spared nerve injury (SNI). METHODS: Neuropathic pain was achieved in a SNI neuropathic pain model by ligating and cutting the common peroneal and tibial branches of the left sciatic nerve, leaving the sural nerve intact. Wistar rats were divided into four groups that received different treatments, i.e., SNI and PRF for 6 min at 45 V (SNI + PRF-45 V), at 60 V (SNI + PRF-60 V), SNI alone, and sham groups. After the SNI surgery, each rat was immediately given the PRF treatment (500 kHz, rate of 2 Hz, 20 ms duration, temperature below 42 °C) on the left sciatic nerve 0.3-0.4 cm proximal to the injured site. The behavioral measurements included mechanical allodynia and cold allodynia of the ipsilateral hind paw and were performed during the 28 days that followed the SNI surgery and PRF treatment. Total extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phospho-ERK1/2 were measured using Western blot in the ipsilateral spinal cord from animals in the different groups. RESULTS: The three groups of rats with nerve injuries manifested a lower paw withdrawal threshold (PWT) in the behavioral measurement of mechanical allodynia and a shorter painful-behavior duration in the cold allodynia test over 28 days. Mechanical allodynia measurement showed that both the PRF-45 V and PRF-60 V treatment groups exhibited a more prominent antiallodynic effect than did the SNI group from days 1 to 28 after surgery. Similarly, in comparison with the SNI group, both the SNI + PRF-45 V and SNI + PRF-60 V groups had significant inhibition on the cold allodynia measurement from days 1 to 28 after surgery. Furthermore, the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the ipsilateral spinal dorsal horn of SNI rats was effectively inhibited in the SNI + PRF-45 V and SNI + PRF-60 V groups for 28 days after surgery. CONCLUSIONS: Immediate PRF application on the proximal nerve injury site provided a significant inhibition of neuropathic pain formation, accompanied by the inhibition of ERK activation.

(+)-Naloxone inhibits morphine-induced chemotaxis via prevention of heat shock protein 90 cleavage in microglia.

BACKGROUND/PURPOSE: Microglia have a crucial role in maintaining neuronal homeostasis in the central nervous system. Immune factors released from microglia have important roles in nociceptive signal transduction. Activation of microglia seems to be a shared mechanism in pathological pain and morphine tolerance because pharmacological attenuation of microglia activation provides satisfactory management in both situations. METHODS: In the present study, we investigated the effect of 1nM (+)-naloxone, which is not an opioid receptor antagonist, on morphine-induced activation of microglia EOC13.31 cells. RESULTS: Our results showed that 1µM morphine enhanced microglia activation and migration, decreased α-tubulin acetylation, and induced heat shock protein 90 (HSP90) fragmentation and histone deacetylase 6 (HDAC6) expression. Morphine-induced α-tubulin deacetylation and HSP90 fragmentation were HDAC6-dependent. Pretreatment with (+)-naloxone (1nM) inhibited morphine-evoked microglia activation and chemotaxis and prevented α-tubulin deacetylation and HSP90 fragmentation by inhibiting HDAC6 expression. CONCLUSION: Based on the findings of the present study, we suggest that (+)-naloxone inhibits morphine-induced microglia activation by regulating HDAC6-dependent α-tubulin deacetylation and HSP90 fragmentation.

Long-Term Anti-Allodynic Effect of Immediate Pulsed Radiofrequency Modulation through Down-Regulation of Insulin-Like Growth Factor 2 in a Neuropathic Pain Model.

Pulsed radiofrequency (PRF) is effective in the treatment of neuropathic pain in clinical practice. Its application to sites proximal to nerve injury can inhibit the activity of extra-cellular signal-regulated kinase (ERK) for up to 28 days. The spared nerve injury (SNI)+ immPRF group (immediate exposure to PRF for 6 min after SNI) exhibited a greater anti-allodynic effect compared with the control group (SNI alone) or the SNI + postPRF group (application of PRF for 6 min on the 14th day after SNI). Insulin-like growth factor 2 (IGF2) was selected using microarray assays and according to web-based gene ontology annotations in the SNI + immPRF group. An increase in IGF2 and activation of ERK1/2 were attenuated by the immPRF treatment compared with an SNI control group. Using immunofluorescent staining, we detected co-localized phosphorylated ERK1/2 and IGF2 in the dorsal horn regions of rats from the SNI group, where the IGF2 protein predominantly arose in CD11b- or NeuN-positive cells, whereas IGF2 immunoreactivity was not detected in the SNI + immPRF group. Taken together, these results suggest that PRF treatment immediately after nerve injury significantly inhibited the development of neuropathic pain with a lasting effect, most likely through IGF2 down-regulation and the inhibition of ERK1/2 activity primarily in microglial cells.

Rosiglitazone attenuates cerebral vasospasm and provides neuroprotection in an experimental rat model of subarachnoid hemorrhage.

BACKGROUND: Glutamate and oxidative stress play important roles after subarachnoid hemorrhage (SAH). The ability to modulate glutamate transporter 1 (GLT-1) and the antioxidative effect of rosiglitazone have been demonstrated. We investigated the neuroprotective effect of rosiglitazone after SAH. METHODS: SAH was induced by double blood injection. The rats were randomly divided into sham, SAH + vehicle, and SAH + rosiglitazone groups and treated with dimethyl sulfoxide, dimethyl sulfoxide, and 6 mg/kg of rosiglitazone, respectively, at 2 and 12 h after SAH induction and then daily for 6 days. Cerebrospinal fluid dialysates were collected 30 min before SAH induction and then daily for 7 days for glutamate measurement. Mortality, body weight, and neurological scores were also measured daily. On day 7 after SAH, the wall thickness and the perimeter of the basilar artery (BA), neuron variability, GLT-1 levels, glial fibrillary acidic protein (GFAP) expression and activity, and malondialdehyde, superoxide dismutase, and catalase activities were also evaluated. RESULTS: Rosiglitazone improved survival (relative risk = 0.325) and neurological functions and reduced neuronal degeneration (5.7 ± 0.8 vs. 10.0 ± 0.9; P < 0.001) compared with the SAH + vehicle group. Rosiglitazone also lowered glutamate levels by 43.5-fold and upregulated GLT-1 expression by 1.5-fold and astrocyte activity by 1.8-fold compared with the SAH + vehicle group. The increase in BA wall thickness was significantly attenuated by rosiglitazone, whereas the perimeter of the BA was increased. In addition, rosiglitazone abated the 1.9-fold increase in malondialdehyde levels and the 1.6-fold increase in catalase activity after SAH. CONCLUSION: Rosiglitazone reduced SAH mortality, neurological deficits, body weight loss, GFAP loss, and cerebral vasospasm by preventing the neurotoxicity induced by glutamate and oxidative stress.

Baicalin ameliorates neuropathic pain by suppressing HDAC1 expression in the spinal cord of spinal nerve ligation rats.

BACKGROUND/PURPOSE: In a recent study, we found that baicalin exhibited a potent analgesic effect on carrageenan-evoked thermal hyperalgesia. The underlining mechanisms may be associated with inhibition of inflammatory mediator overproduction, including proinflammatory cytokines, nitric oxide (NO), and prostaglandin E2 (PGE2). In the present study, we examined the effect of baicalin on the antinociceptive effect of morphine and histone deacetylase 1 (HDAC1) expression in the spinal cord dorsal horn in neuropathic pain rats. METHODS: Neuropathic pain was induced by tight ligation of the left L5 spinal nerve of the rats. An intrathecal catheter was implanted for drug administration. Nociception was assessed by using the plantar test with the Hargreaves radiant heat apparatus, and the von Frey test with the dynamic plantar anesthesiometer. Spinal cords were removed for histone acetyl-H3 and HDAC1 western blot analysis at the end of the nociceptive assessment. RESULTS: The results showed that hyperalgesia and allodynia were observed in the spinal nerve ligated (SNL) left hindlimb; it was companied by histone-H3 deacetylation and HDAC1 overexpression on the ipsilateral side of the spinal cord dorsal horn. Intrathecal injection of baicalin (10 µg) significantly attenuated the allodynia and hyperalgesia, and enhanced the antinociceptive effect of morphine (15 µg). Moreover, baicalin reversed the histone-H3 acetylation and suppressed HDAC1 expression on the ipsilateral side of the spinal cord dorsal horn of SNL rats. CONCLUSION: The present findings suggest that baicalin can ameliorate neuropathic pain by suppressing HDAC1 expression and preventing histone-H3 acetylation in the spinal cord dorsal horn of SNL rats.

Early intraarticular injection of hyaluronic acid attenuates osteoarthritis progression in anterior cruciate ligament-transected rats.

SUBJECT: Hyaluronic acid (HA) is widely used to relieve the symptoms of osteoarthritis (OA). An association of reduction of glutamate content with the synovial fluid of OA rats was reported previously. DESIGN: Anterior cruciate ligament transaction (ACLT) was performed on one knee in male Wistar rats, the other knee was assigned to sham control and HA or saline was injected intraarticularly into the ACLT knee from week 3 to week 7. Knee dialysate was collected for amino acid measurement at week 20. Morphology and histopathology of the femoral medial condyles and synovium were examined and evaluated using Mankin and synovitis scores. RESULTS: HA injection provided better cartilage (3.38 ± 0.03 vs. 5.45 ± 0.0.02) and synovial condition (3 ± 0.02 vs. 6.03 ± 0.02) than saline controls. Moreover, HA injection reduced the concentration of glutamates in knee dialysates compared to saline controls (1.11 ± 0.14-folds and 2.21 ± 0.19-folds of the sham-operated knee, respectively). Cystine/glutamate antiporter system [Formula: see text] expression was significantly downregulated in the saline group, but not in the HA group (0.32 ± 0.08-folds and 0.71 ± 0.10-folds of the sham-operated knee, respectively). CONCLUSION: Early intraarticular injection of HA attenuates the progression of cartilage destruction in the ACLT knee, and the downregulation of the cystine/glutamate antiporter system [Formula: see text] was accompanied by the progression of OA.

Intrathecal ultra-low dose naloxone enhances the antihyperalgesic effects of morphine and attenuates tumor necrosis factor-α and tumor necrosis factor-α receptor 1 expression in the dorsal horn of rats with partial sciatic nerve transection.

BACKGROUND: Glutamate homeostasis and microglia activation play an important role in the development and maintenance of neuropathic pain. We designed this investigation to examine whether ultra-low dose naloxone administered alone or in combination with morphine could alter the concentration of the excitatory amino acids (EAAs) glutamate and aspartate, as well as the expression of tumor necrosis factor-α (TNF-α) and its receptors (TNFR1 and TNFR2) in the spinal cord dorsal horn of rats with partial sciatic nerve transection (PST). METHODS: Male Wistar rats underwent intrathecal catheter implantation for drug delivery and were divided in 7 groups: sham-operated + saline (sham), PST + saline (S), PST + 15 ng naloxone (n), PST + 15 µg naloxone (N), PST + 10 µg morphine (M), PST + 15 ng naloxone + 10 µg morphine (Mn), PST + 15 µg naloxone + 10 µg morphine (MN). Thermal withdrawal latency and mechanical withdrawal threshold, TNF-α and TNFR expression in the spinal cord and dorsal root ganglia, and EAAs glutamate and aspartate concentration in cerebrospinal fluid dialysates were measured. RESULTS: Ten days after PST, rats developed hyperalgesia (P < 0.0001) and allodynia (P < 0.0001), and increased TNF-α (P < 0.0001) and TNFR1 expression (P = 0.0009) were measured in the ipsilateral spinal cord dorsal horn. The antihyperalgesic and antiallodynic effects of morphine (10 µg) were abolished by high-dose naloxone (15 µg; P = 0.0031) but enhanced by ultra-low dose naloxone (15 ng; P = 0.0015), and this was associated with a reduction of TNF-α (P < 0.0001) and TNFR1 (P = 0.0009) expression in the spinal cord dorsal horn and EAAs concentration (glutamate: P = 0.0001; aspartate: P = 0.004) in cerebrospinal fluid dialysate. Analysis of variance (ANOVA) or Student t test with Bonferroni correction were used for statistical analysis. CONCLUSIONS: Ultra-low dose naloxone enhances the antihyperalgesia and antiallodynia effects of morphine in PST rats, possibly by reducing TNF-α and TNFR1 expression, and EAAs concentrations in the spinal dorsal horn. Ultra-low dose naloxone may be a useful adjuvant for increasing the analgesic effect of morphine in neuropathic pain conditions.

Intrathecal glutamate release during hindlimb tourniquet inflation and femoral artery occlusion in rats.

BACKGROUND/PURPOSE: A tourniquet is commonly used in limb surgery. Tourniquet inflation after a period of time may produce painful sensation. While the mechanisms of tourniquet-induced pain are still unknown, two components, pressure and ischemia, have been proposed. In this study, in vivo microdialysis was used to detect changes in intrathecal glutamate, an excitatory amino acid highly relevant to pain transmission, following hindlimb tourniquet application and femoral artery occlusion in the rat. METHODS: Male Wistar rats were used. For the tourniquet study, 6 rats of the study group received 30 minutes right hindlimb tourniquet inflation and another 6 rats as the control group received only tourniquet application without inflation. In the femoral artery occlusion study, 6 rats of the study group received 30 minutes right femoral artery occlusion and another 6 rats as the control group received only sham operation without femoral artery occlusion. Cerebrospinal fluid dialysates were collected prior to, during, and after tourniquet application or femoral artery occlusion. Glutamate was measured by HPLC. RESULTS: A significant increase in intrathecal glutamate release was found during the tourniquet inflation period, and it returned to baseline after tourniquet deflation. No change of glutamate release was noted during femoral artery occlusion or after femoral artery reperfusion. CONCLUSION: The intrathecal glutamate release was increased by the hindlimb tourniquet inflation, but not influenced by femoral artery occlusion in the rat.