Ferroptosis inhibitor ferrostatin-1 attenuates morphine tolerance development in male rats by inhibiting dorsal root ganglion neuronal ferroptosis.

Background: Ferrostatin-1 and liproxstatin-1, both ferroptosis inhibitors, protect cells. Liproxstatin-1 decreases morphine tolerance. Yet, ferrostatin-1's effect on morphine tolerance remains unexplored. This study aimed to evaluate the influence of ferrostatin-1 on the advancement of morphine tolerance and understand the underlying mechanisms in male rats. Methods: This experiment involved 36 adult male Wistar albino rats with an average weight ranging from 220 to 260 g. These rats were categorized into six groups: Control, single dose ferrostatin-1, single dose morphine, single dose ferrostatin-1 + morphine, morphine tolerance (twice daily for five days), and ferrostatin-1 + morphine tolerance (twice daily for five days). The antinociceptive action was evaluated using both the hot plate and tail-flick tests. After completing the analgesic tests, tissue samples were gathered from the dorsal root ganglia (DRG) for subsequent analysis. The levels of glutathione, glutathione peroxidase 4 (GPX4), and nuclear factor erythroid 2-related factor 2 (Nrf2), along with the measurements of total oxidant status (TOS) and total antioxidant status (TAS), were assessed in the tissues of the DRG. Results: After tolerance development, the administration of ferrostatin-1 resulted in a significant decrease in morphine tolerance (P < 0.001). Additionally, ferrostatin-1 treatment led to elevated levels of glutathione, GPX4, Nrf2, and TOS (P < 0.001), while simultaneously causing a decrease in TAS levels (P < 0.001). Conclusions: The study found that ferrostatin-1 can reduce morphine tolerance by suppressing ferroptosis and reducing oxidative stress in DRG neurons, suggesting it as a potential therapy for preventing morphine tolerance.

Attenuation of acute postoperative pain and opioid requirement with the use of magnesium sulfate in patients undergoing limb amputations.

OBJECTIVE: To compare the effects of magnesium sulphate on the total dose of intravenous morphine consumption postoperatively following limb amputations along with rescue analgesia requirement, pain scores and side effects. METHODS: This prospective, triple-blinded, randomised controlled study was conducted from October 2021 to May 2022 at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised of patients scheduled for limb amputations. They were randomised into 2 equal groups. The anaesthesia protocol was uniform for all patients. Intervention group A was administered 30mg/kg loading dose and 10mg/kg/hr maintenance dose of magnesium sulphate intravenously, while patients in control group B received the same amount of plain isotonic saline. Morphine consumption, including that used for rescue analgesia and patient-controlled analgesia, was measured for 24 hours postoperatively. Numeric rating scale was used for the evaluation of postoperative pain in both groups at 15min, 1h, 2h, at discharge from the post-anaesthesia care unit and at 12h and 24h in the ward. Data was analysed using SPSS 23. RESULTS: Of the 24 patients enrolled, the study was completed by 20(83.33%). There were 10(50%) patients in group A; 8(40%) males and 2(20%) females with mean age 24.8±14.14 years and mean surgery time 130.5±47.86 minutes. There were 10(50%) patients in group B; 8(40%) males and 2(20%) females with mean age 23.2±7.4 years and mean surgery time 117±23.85 minutes (p>0.05). Total morphine used over 24 hours in group A was 16±3.1 mg compared to 29.6±11.2 mg in group B (p<0.05). The time for first use of patient-controlled analgesia after arriving in the postanaesthesia care unit was significantly delayed in group A (72.2±24.95 minutes) compared to that in group B (25±26.68 minutes) (p<0.05). Pain scores were significantly higher in the group B at 15min compared to group A (p<0.05), but not at the rest of the time points (p>0.05). CONCLUSIONS: Intravenous magnesium sulphate proved to be effective in lowering postoperative opioid requirement following limb amputations.

Postoperative Cesarean Section Pain Management Using Transversus Abdominis Plane Block Versus Intrathecal Morphine: A Systematic Review and Meta-analysis.

PURPOSE: Compare and evaluate the effectiveness of transversus abdominis plane (TAP) block versus intrathecal morphine (ITM) on elective postcesarean section pain, opioid consumption, and related side effects. DESIGN: Systematic review and meta-analysis. METHODS: A search for evidence was conducted in PubMed, Google Scholar, CINAHL, Cochrane Collaboration Database, UpToDate, Health Source, and gray literature. Only randomized controlled trials (RCTs) were included in the study. The methodological quality of evidence assessment was conducted using the Risk of Bias and Grades of Recommendation, Assessment, Development, and Evaluation system. The meta-analysis used Review Manager (RevMan 5.4, The Cochrane Collaboration). FINDINGS: A total of 11 RCTs involving 1,129 patients were analyzed. Compared to ITM, TAP has a similar effect on static (mean difference [MD]; 0.37; 95% confidence interval [CI], -0.04 to 0.79; P = .08) and dynamic pain scores (MD, 0.43; 95% CI, -0.06 to 0.92; P = .09) within the first 48 hours after surgery. Additionally, the TAP block had a lower incidence of postoperative nausea and vomiting (risk ratio, 0.45; 95% CI, 0.31 to 0.66; P < .0001) and increased opioid consumption (MD, 6.78; 95% CI, 3.79 to 9.77; P < .00001). Overall, TAP block and ITM did not differ in the time to first to rescue analgesia, incidence of sedation, and pruritus. CONCLUSIONS: Evidence suggests that TAP blocks are equivalent to ITM in pain scores and more effective at lowering the incidence of postoperative nausea and vomiting, yet ITM has been shown to be more effective in reducing postoperative opioid consumption.

BACLOFEN PREVENTS MORPHINE REWARDING EFFECTS AND ASSOCIATED BIOCHEMICAL ALTERATIONS IN MALE AND FEMALE MICE.

Previous studies from our laboratory have shown sex differences in the behavioral, molecular, and neurochemical manifestations of morphine withdrawal and they were related to an increased sensitivity to morphine effects in males. In addition, we observed an interaction between the GABAergic and opioid systems that could also be sex-dependent. Baclofen, a GABAB receptor agonist, prevented the somatic expression and the molecular and neurochemical changes induced by morphine withdrawal syndrome in mice. On the contrary, little is known about baclofen effects in the rewarding properties of morphine in male and female mice. The present study aimed to explore the effect of baclofen (1, 2 and 3 mg/kg, i.p.) pretreatment in the rewarding effects induced by morphine (7 mg/kg, s.c.) and its effect on c-Fos and brain-derived neurotrophic factor (BDNF) expression induced by the rewarding properties of morphine in prepubertal male and female mice. Baclofen (2 mg/kg) pretreatment prevented the rewarding effects of morphine only in male mice, while baclofen (3 mg/kg) reduced these effects in both sexes. Moreover, the rewarding effects of morphine were associated with a decrease of BDNF and c-Fos expression cingulate cortex, nucleus accumbens shell, cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) areas of the hippocampus only in male mice. In addition, baclofen pretreatment prevented these changes in BDNF, but not in c-Fos expression. In conclusion, our results show that GABAB receptors have a regulatory role in the rewarding effects of morphine that could be of interest for a potential future therapeutic application in opioid use disorders.

Effects of Thymbra spicata extract and Thymol on morphine withdrawal syndrome in mice (insights to the liver function, antioxidant, and behavioral responses).

Safe chemicals for drug withdrawal can be extracted from natural sources. This study investigates the effects of clonidine and Thymbra spicata extract (TSE) on mice suffering from morphine withdrawal syndrome. Thymol, which is the active constituent in TSE, was also tested. A total of 90 mice were divided into nine groups. Group 1 was the control group, while Group 2 was given only morphine, and Group 3 received morphine and 0.2 mg/kg of clonidine. Groups 4-6 were given morphine along with 100, 200, and 300 mg/kg of TSE, respectively. Groups 7-9 received morphine plus 30, 60, and 90 mg/kg of Thymol, respectively, for 7 days. An oral naloxone challenge of 3 mg/kg was used to induce withdrawal syndrome in all groups. Improvement of liver enzyme levels (aspartate aminotransferase, alkaline phosphatase, and alanine transaminase) (p < .01) and behavioral responses (frequencies of jumping, frequencies of two-legged standing, Straub tail reaction) (p < .01) were significantly observed in the groups receiving TSE and Thymol (Groups 4-9) compared to Group 2. Additionally, antioxidant activity in these groups was improved compared to Group 2. Nitric oxide significantly decreased in Groups 4 and 6 compared to Groups 2 and 3 (p < .01). Superoxide dismutase increased dramatically in Groups 5, 8, and 9 compared to Groups 2 and 3 (p < .01). Groups 5-9 were significantly different from Group 2 in terms of malondialdehyde levels (p < .01). Certain doses of TSE and Thymol were found to alleviate the narcotics withdrawal symptoms. This similar effect to clonidine can pave the way for their administration in humans.

Effect of repeated intraperitoneal injections of different concentrations of oxycodone on immune function in mice.

Background: The effect of oxycodone as an opioid receptor agonist on immune function is still controversial. In this study, we investigated the possible effects of oxycodone on immune function in mice and its possible mechanisms of action. Methods: By repeated intraperitoneal injections of 25 mg/kg morphine and 5 mg/kg, 20 mg/kg, and 60 mg/kg oxycodone, we assessed possible changes in the number of splenic lymphocytes and inflammatory cytokines in the serum of mice. CD4+ T cells and CD8+ T cells were sorted from the spleen to observe whether the expression levels of opioid receptors and downstream signals were altered. Results: Repeated administration of oxycodone at a dose above 20 mg/kg resulted in significant weight loss. Repeated administration of oxycodone exhibits significant dose-dependent reduction in CD4+ T cells, with little effect on CD8+ T cells and little effect on inflammatory cytokine levels. Low- and intermediate-dose oxycodone increased the mRNA expression level of MOR, KOR, and DOR to varying degrees. Moreover, oxycodone increases the mRNA expression levels of the TLR4 signaling pathway to varying degrees. Conclusion: Repeated intraperitoneal injection of oxycodone induces immunosuppression in mice.

Additive Anticonvulsive Effects of Sumatriptan and Morphine on Pentylenetetrazole-Induced Clonic Seizures in Mice.

Background and Purpose: Sumatriptan protects the brain from damage and enhance the anti-seizure effect of morphine. There is evidence that nitric oxide (NO) may mediate these effects of both drugs. In the present study, we investigated the effects of sumatriptan (0.1-20 mg/kg, intraperitoneal [i.p.]) and morphine (0.1-20 mg/kg, i.p.) alone or in combination on seizure thresholds in an in vivo model of seizure in mice. Using various NO synthase inhibitors as well as the NO precursor, we assessed possible involvement of NO signaling in these effects. Methods: Clonic seizures were induced in male Naval Medical Research Institute mice by intravenous administration of pentylenetetrazol (PTZ). Results: Acute sumatriptan administration exerted anti-convulsive effects at 0.5 (p<0.01) and 1 mg/kg (p<0.05), but pro-convulsive effects at 20 mg/kg (p<0.05). Morphine had anti-convulsive effects at 0.5 (p<0.05) and 1 mg/kg (p<0.001), but exerted pro-convulsive effect at 20 mg/kg (p<0.05). Combination treatment with sub-effective doses of sumatriptan (0.1 mg/kg) and morphine (0.1 mg/kg) significantly (p<0.05) exerted an anti-convulsive effect. Co-administration of the NO precursor L-arginine (60 mg/kg) with sub-effective doses of sumatriptan and morphine significantly (p<0.05) increased seizure threshold compared with sumatriptan alone, but not sumatriptan+morphine group. While concomitant administration of either the non-selective NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (5 mg/kg) or the selective inducible NOS inhibitor aminoguanidine (50 mg/kg) with combined sub-effective doses of morphine and sumatriptan produced significant anticonvulsive effects, concomitant administration with the selective neuronal NOS inhibitor 7-nitroindazole (30 mg/kg) inhibited this effect. Conclusions: Our data suggest a possible role for the NO signaling in the anticonvulsive effects of combined sumatriptan and morphine on the PTZ-induced clonic seizures in mice.

Comparison of patient-controlled epidural analgesia and epidural morphine for post-cesarean section analgesia: experience from a tertiary center in China.

PURPOSE: To compare patient-controlled epidural analgesia (PCEA) and epidural morphine (EM) for post-cesarean section analgesia in real-world experience from China. METHODS: Parturients receiving one dose of EM (1-2 mg), PCEA, or both EM and PCEA from Peking Union Medical College Hospital were retrospectively recruited. Logistic models were used to identify risk factors. RESULTS: Of 1079 parturients enrolled, 919 (85.2%) parturients received only EM, 105 (9.7%) parturients received PCEA, and 55 (5.1%) parturients received both EM and PCEA. Significantly more parturients from EM group requested supplementary analgesia than those from PCEA and PCEA + EM group (583, 63.4% vs 52, 49.5% vs 25, 45.5%, P = 0.001) with more times of supplementary analgesia (1, IQR: 0-2 vs 0, IQR: 0-1 vs 0, IQR: 0-1 times, P < 0.001) and larger amounts of nonsteroidal anti-inflammatory drugs (NSAIDs) (50, IQR: 0-100 mg vs 0, IQR: 0-50 mg vs 0, IQR: 0-50 mg, P < 0.001). In multivariable Logistic regression for the supplementary analgesia risk, the application of PCEA (OR: 0.557, 95%CI 0.396-0.783, P = 0.001) and the use of NSAIDs intraoperatively (OR: 2.996, 95%CI 1.811-4.957, P < 0.001) were identified as independent predictors. A total of 1040 (96.4%) patients received prophylactic antiemetic therapy during surgery. Only 13 (1.2%) and 7 (0.6%) patients in our cohort requested antiemetic and antipruritic drugs, respectively. CONCLUSION: The use of PCEA was an independent protective factor for supplementary analgesia during the post-cesarean section. Prophylactic antiemetic therapy may reduce the side effects of post-cesarean analgesia.

Efficacy and Safety of Intrathecal Morphine for Cesarean Delivery: A Narrative Review.

PURPOSE OF REVIEW: Pain management is a critical aspect of care during and following a cesarean delivery. Without proper control of pain, individuals can experience poor mobility, increased thromboembolic events, and difficulty caring for the neonate in the postpartum period. There have been multiple methods for pain management for cesarean delivery and intrathecal morphine (ITM) has emerged as a prominent option for post-operative analgesia due to its efficacy, safety, and potential benefits over other treatments. This review analyzes data on efficacy, side effects, and safety of ITM and the pain control alternatives. RECENT FINDINGS: A comprehensive literature review was conducted to compare ITM with other analgesic techniques in post-cesarean patients. ITM was found to be as effective or better than other analgesic options, including bilateral quadratus lumborum block (QLB), opioid-free epidural analgesia (CSEA-EDA), and intravenous fentanyl. One study found that both ITM and oral analgesia were effective in pain control and that ITM caused fewer breakthrough pain events but had a longer duration and a greater rate of side effects than oral opioid analgesia. Commonly observed side effects of intrathecal opioids include nausea, vomiting, pruritus, and urinary retention, and it is thought that the adverse effects from intrathecal administration of opioids are short-lived. ITM may provide a decreased risk of DVT and coagulation by decreasing lower extremity weakness and numbness, thereby decreasing recovery time and increasing mobility. ITM is a safe and effective option for post-cesarean analgesia, with comparable pain relief to alternative forms of pain control, and side effects that are generally manageable. Further research is warranted to explore beneficial combinations with other methods of pain management and optimal dosing strategies.

Evaluation of the Effects of Opium on the Expression of SOX2 and OCT4 in Wistar Rat Bladder.

BACKGROUND: Bladder cancer is a malignancy greatly affected by behavioral habits. The aim of this study was to examine the effect of opium on changes in the expression of OCT4 and SOX2 in the bladder tissue of rats. METHOD: Thirty six rats were divided into six groups: 24 rats in the addicted group received morphine and opium for 4 months with 12 rats in the control group. Blood testing was done for the evaluation of CBC, MDA, and TAC. The bladder tissue was removed and checked by histopathological examination. All total RNA was extracted, then cDNAs were synthesized and the OCT4 and SOX2 gene expressions were evaluated by Real-time PCR. RESULTS: The OCT4 mRNA expression level in the opium group of rats was significantly increased compared to the control group (13.5 and 6.8 fold in males and females respectively). Also, in the morphine group, similar augmentation was detected (3.8 and 6.7 fold in males and females respectively). The SOX2 mRNA over-expression level was seen in the morphine group of both genders as compared to the control group (3.7 and 4.2 fold in male and female respectively) but in the opium group, enhancement of mRNA level was seen only in males (6.6 fold). Opium increases both OCT4 and SOX2 expression more than morphine in male rats, but in female rats, SOX2 is increased more by morphine. CONCLUSION: Over expression of OCT4 and SOX2 was observed in rats treated with opium and morphine. Increased OCT4 and SOX2 expression was seen in opium-treated male rats, but in female rats, SOX2 was increased more by morphine.

Fragile Treg cells: Traitors in immune homeostasis?

Regulatory T (Treg) cells play a key role in maintaining immune tolerance and tissue homeostasis. However, in some disease microenvironments, Treg cells exhibit fragility, which manifests as preserved FoxP3 expression accompanied by inflammation and loss of immunosuppression. Fragile Treg cells are formatively, phenotypically and functionally diverse in various diseases, further complicating the role of Treg cells in the immunotherapeutic response and offering novel targets for disease treatment by modulating specific Treg subsets. In this review, we summarize findings on fragile Treg cells to provide a framework for characterizing the formation and role of fragile Treg cells in different diseases, and we discuss how this information may guide the development of more specific Treg-targeted immunotherapies.

Low dose of morphine to relieve dyspnea in acute respiratory failure: the OpiDys double-blind randomized controlled trial.

BACKGROUND: Morphine relieves dyspnea in various clinical circumstances. Whether or not this applies to patients admitted to intensive care units (ICUs) for acute respiratory failure (ARF) is unknown. We evaluated the efficacy and safety of low-dose morphine on dyspnea in patients admitted to the ICU for ARF. METHODS: In this single-center, double-blind, phase 2, randomized, controlled trial, we assigned non-intubated adults admitted to the ICU for ARF with severe dyspnea, defined by a visual analog scale for dyspnea (dyspnea-VAS) from zero (no dyspnea) to 100 mm (worst imaginable dyspnea) ≥40 mm, to receive a low dose of Morphine Hydrochloride (intravenous titration followed by subcutaneous relay) or Placebo. All patients received standard therapy, including etiological treatment and non-invasive respiratory support. RESULTS: Twenty-two patients were randomized, 11 in each group. The average dyspnea (median [interquartile range]) over 24 hours did not significantly differ between the two groups (40 [25 - 43] mm in the Morphine group vs. 40 [36 - 49] mm in the Placebo group, p=0.411). Dyspnea-VAS was lower in the Morphine group than in the Placebo group at the end of intravenous titration (30 [11 - 30] vs. 35 [30 - 44], p=0.044) and four hours later (18 [10 - 29] vs. 50 [30 - 60], p=0.043). The cumulative probability of intubation was higher in the Morphine group than in the Placebo group (p=0.046) CONCLUSION: In this phase 2 pilot trial, morphine did not improve 24-hour average dyspnea in adult patients with ARF, even though it had a statistically significant immediate effect. Of concern, Morphine use was associated with a higher intubation rate. TRIAL REGISTRATION: The protocol was declared on the ClinicalTrial.gov database (no. NCT04358133) and was published in September 2022.

Low-dose ketamine as an adjunct to morphine: A randomized controlled trial among patients with and without current opioid use.

BACKGROUND: Pain is a common complaint among patients presenting to the emergency department (ED), yet pain treatment is frequently suboptimal. The aim of this study was to determine the effectiveness of low-dose ketamine (LDK) as an adjunct to morphine versus morphine alone for treatment of acute pain among ED patients with and without current opioid use. METHODS: Adult patients presenting with acute pain of ≥5 on a numeric rating scale (0-10) who were deemed by their treating ED physician to require intravenous opioids were randomized to receive either 0.1 mg/kg ketamine (treatment group) or isotonic saline (placebo) as an adjunct to morphine. Patients with and without current opioid use were randomized separately. Pain was measured at baseline (T0) and 10, 20, 30, 45, 60, and 120 min after randomization. The primary outcome was pain reduction from T0 to T10. Secondary outcomes included pain intensity over 120 min, need of rescue opioids, side effects, and patient and provider satisfaction. RESULTS: A total of 116 patients were included from May 2022 to August 2023. Median (IQR) age was 51 (36.5-67) years; 58% were male and 36% had current opioid use. Pain reduction from T0 to T10 was greater in the LDK group (4 [IQR 3-6]) compared to the placebo group (1 [IQR 0-2]; p = 0.001). Pain intensity was lower in the LDK group at T10, T20, and T30, compared to the placebo group. There was a higher risk of nausea, vomiting, and dissociation in the LDK group during the first 10 min. CONCLUSIONS: LDK may be effective as an adjunct analgesic to morphine for short-term pain relief in treatment of acute pain in the ED for both patients with and without current opioid use.

The Effect of Antinociceptive Dose of Morphine on Cell Therapy in Rats with Spinal Cord Injury.

Spinal cord injury (SCI) is a sensory-motor injury. Today, combined treatments such as cell therapy along with drug therapy and their interactions are of interest. Morphine is an opioid drug used to relieve intolerable pain. This study aims to evaluate the impact of an antinociceptive dose of morphine (with minimal tolerance/dependence but effective pain relief) on cell therapy in SCI. The antinociceptive dose of morphine was determined in rats with SCI through the Hargreaves and naloxone-induced morphine withdrawal tests. The rats were then allocated to 5 groups: laminectomy, SCI, SCI + Morphine, SCI + cell therapy, SCI + Morphine + cell therapy. The antinociceptive dose (5 mg/kg) was administered on days 1, 4, 10, and 13 (i.p.) post-SCI. On day 7, Neural-like stem cells derived from adipose tissue were transplanted intraspinally into the injured animals, and they were monitored for 12 weeks. The outcomes were assessed using the BBB test, somatosensory evoked potential (SSEP), and histology. The BBB test indicated that morphine significantly hindered functional recovery post-cell transplantation compared to animals receiving only cell therapy (p < 0.05). In the SSEP test, the analysis of amplitude and latency of waves did not reveal a significant difference (p > 0.05). The histological results showed that cell therapy reduced the cavity size post-SCI, while morphine had no significant impact on it. Morphine at the antinociceptive dose significantly impairs motor recovery despite cell therapy. Nonetheless, there was no significant difference between groups in terms of sensory pathway outcomes.

Evaluation of Postoperative Efficacy and Safety of Celecoxib in Children Hospitalized After Adenotonsillectomy.

OBJECTIVE: The choice of optimal analgesia following an adenotonsillectomy is a clinical issue because of the risk of respiratory depression and bleeding. The objective of this study was to assess the effect of celecoxib on opioid use and pain scores in children hospitalized after adenotonsillectomy and to document its adverse effects. METHODS: This retrospective study was conducted in a tertiary care pediatric hospital. We compared a group of subjects aged 1 to 17 years who were prescribed celecoxib and opioids between January 2017 and June 2020 following an adenotonsillectomy during a 3-day or less hospitalization to a group of matched controls for sex, age, and length of stay who were prescribed opioids. RESULTS: A total of 228 patients were identified (76 in the celecoxib + opioids group, 152 in the control group). Opioid use, in oral morphine equivalent daily dose, was lower in the celecoxib + opioids group at 0 to 24 hours of hospitalization (0.15 vs 0.20 mg/kg/day, p = 0.05). Initiating celecoxib within 24 hours of surgery (n = 60) significantly reduced opioid requirement for up to 48 hours compared with controls (0-24 hours: 0.12 vs 0.20 mg/kg/day, p = 0.002; 25-48 hours: 0.02 vs 0.09 mg/kg/day, p = 0.001). A shorter length of stay was observed for patients receiving celecoxib + opioids during the first 24-hour post--operative period (27 vs 32 hours, p = 0.01). With celecoxib use, no significant change in pain scores and occurrence of adverse effects including bleeding was found. CONCLUSIONS: Using celecoxib early after an adenotonsillectomy has reduced both opioid use and duration of hospital stay without increasing adverse effects or bleeding.

Regional anesthesia is safe for use in intramedullary nailing of low-energy tibial shaft fractures.

PURPOSE: The purpose was to compare perioperative outcomes of patients who underwent general or regional anesthesia for intramedullary (IM) nailing of tibial shaft fractures (TSFs). METHODS: Retrospective chart review was performed on a consecutive series of low-energy TSF patients who presented to a single academic medical center and a level 1 trauma center who underwent operative repair with a reamed IM nail. Collected information included demographics, injury information, anesthesia type (general or regional i.e. peripheral nerve block), intra-operative opiate consumption (converted to morphine milliequivalents [MME], and post-operative pain visual-analog scale [VAS] pain scores. Patients were divided into 3 groups based on the type of anesthesia received and univariate analysis was performed to compare the 3 groups. RESULTS: Seventy-six patients were included, with an average age of 44.47±16.0 years. There were 38 (50 %) who were administered general anesthesia and 38 (50 %) who were administered regional anesthesia in the form of a peripheral nerve block. There were no differences between the groups with respect to demographics, medical co-morbidities, rate of open fractures or AO/OTA fracture classification. Regional anesthesia patients received less intra-operative MME than general anesthesia patients (17.57±10.6, 28.96±13.8, p < 0.001). Patients who received regional anesthesia also spent less time in the operating room, received less MME on post-operative day 1, and ambulated further on post-operative day 1, however none of these differences were statistically significant. There were no cases of missed post-operative compartment syndrome or complications related to the administration of the peripheral nerve block. CONCLUSIONS: Regional anesthesia in TSF surgery received less intra-operative opioid requirements, without any untoward effects. LEVEL OF EVIDENCE: Therapeutic Level III.

20- Deoxyingenol attenuate morphine-induced hippocampus neurotoxicity and memory impairments in rats.

Objective: The present study aimed to see if 20-Deoxyingenol(20-DOI) could protect hippocampus neurons from the neurotoxic effects of morphine and reduce memory loss in rats. Method: Male Wistar rats were given morphine hydrochloride (45 mg/kg, sc, four weeks) and 20-DOI (10, 20 mg/kg, ip., coadministered with morphine) for the Morris Water Maze (MWM) test to investigate the effects of 20-DOI on spatial learning and memory. Western blotting was used to evaluate the expression of the hippocampal CA1 region of the cleaved caspase-3, Bax, and Bcl2 proteins and so on. Moreover, these assays were used to evaluate the expression of superoxide dismutase (SOD)2, heme oxygenase 1(HO1) protein, and glutathione peroxidase (GPx) activity within the hippocampus CA1 area. Results: The administration of 20-DOI (10 and 20 mg/kg) to morphine-treated mice enhanced spatial learning and reduced memory deficits. Additionally, 20-DOI treatment reduced apoptosis and oxidative stress in the hippocampal CA1 region of morphine-treated rats. Moreover, 20-DOI improved the autophagy level of the hippocampal CA1 area of morphine-treated rats using Transcription factor EB (TFEB), and 20-DOI prevented spatial learning and memory impairment in morphine-treated rats. The current observation could be partially due to the inhibition of neuronal apoptosis and oxidative stress in the hippocampal CA1 region of rats treated with morphine and the improved autophagy in this region. Conclusions: 20-DOI attenuated morphine administration in rats with chronic disease caused spatial learning and memory dysfunction. These mechanistic effects could be partially related to 20-DOI protecting the CA1 region of rat hippocampal neurons from the morphine-induced oxidative stress, apoptosis, and autophagy through TFEB.

Effects of Acetic Acid and Morphine in Shore Crabs, Carcinus maenas: Implications for the Possibility of Pain in Decapods.

Noxious chemicals, coupled with morphine treatment, are often used in studies on pain in vertebrates. Here we show that injection of morphine caused several behavioural changes in the crab, Carcinus maenas, including reduced pressing against the sides of the enclosure and more rubbing and picking at the mouth parts and, at least for a short time, more defensive displays. Subsequent injection of acetic acid into one rear leg caused rubbing of the injected leg and the injected leg was held vertically off the ground. These activities directed at or involving the specific leg are consistent with previous observations of directed behaviour following noxious stimuli and are consistent with the idea that decapods experience pain. Further, acetic acid but not injection of water induced autotomy of the injected leg in these animals. Because autotomy is temporally associated with directed behaviour, it is possible that the autotomy is a pain-related response. Acetic acid is clearly a noxious substance when applied to decapods. However, morphine had no effect on the activities associated with acetic acid injection and thus there is no evidence for an analgesic effect. Further, the injection of acetic acid did not interfere with behavioural effects of morphine. The activities directed towards the site of injection are like those observed with injection, or with external application, of various noxious substances and the present study adds to a growing body of knowledge about possible pain in decapods.