Mechanistic insights into the analgesic and anti-inflammatory effects of alcoholic extracts from Curcuma longa

Background: Aim of the study was to scientifically validate the traditional Indian claims of Curcuma longa's (turmeric) antinociceptive (pain-relieving) and anti-inflammatory effects. Methods: The alcoholic extract of C. longa was tested in three rodent nociceptive models: acetic acid-induced writhing: examines visceral pain, formalin test: evaluates both acute and chronic neurogenic and inflammatory pain and tail immersion test to assess thermal pain. The extract's effects were compared to a control group and morphine (reference drug). Results: C. longa extract significantly reduced abdominal constrictions in the acetic acid test (59.36% inhibition). In the formalin test, the extract significantly decreased paw licking response time in both early (54.12% inhibition) and late phases (78.59% inhibition). C. longa extract significantly increased the tail flick reaction time in the immersion test, indicating pain relief. Conclusions: This study confirms the antinociceptive and anti-inflammatory activities of C. longa, providing scientific evidence for its traditional use in pain management.

Efectividad de la anestesia subaracnoidea con morfina como tratamiento del dolor postoperatorio en cesárea

Fundamento el dolor postoperatorio se considera un dolor con limitaciones de tiempo, a menudo mal controlado. Su manejo representa un gran desafío, ya que la analgesia postoperatoria debe brindar a la madre un control adecuado de este, y a su vez facilitar la atención del bebé. Objetivo evaluar la efectividad de la anestesia subaracnoidea con morfina como tratamiento del dolor postoperatorio en cesárea. Métodos estudio descriptivo y transversal, realizado en el Hospital General Docente Martín Chang Puga, del municipio de Nuevitas, provincia de Camagüey, entre enero de 2021 y diciembre de 2022. La muestra estuvo conformada por 36 pacientes a las cuales se aplicó anestesia subaracnoidea con lidocaína hiperbárica más morfina para la cesárea. Resultados predominó la edad comprendida entre 27-31 años. El 63,9 % de las cesareadas no refirió dolor postoperatorio. Casi la mitad de la población (47,2 %) estudiada presentó efectos secundarios con el uso de la morfina intratecal, principalmente el prurito. El 80,5 % expresó satisfacción con la analgesia postoperatoria. Conclusiones la mayoría de las pacientes encontraron satisfacción con el tratamiento analgésico, a pesar la presencia de efectos adversos, de modo que el uso de morfina intratecal es efectivo en el manejo del dolor poscesárea.

Foundation Postoperative pain is considered time-limited pain, often poorly controlled. Its management represents a great challenge, since postoperative analgesia must provide the mother with adequate control, and at the same time facilitate care for the baby. Objective to evaluate the effectiveness of subarachnoid anesthesia with morphine as a treatment for postoperative pain in cesarean section. Methods descriptive and cross-sectional study carried out at the Martín Chang Puga General Teaching Hospital, in the Nuevitas municipality, Camagüey province, between January 2021 and December 2022. 36 patients to whom subarachnoid anesthesia was applied with Hyperbaric lidocaine plus morphine for cesarean section were considered as the sample. Results the age between 27-31 years predominated. 63.9% of cesarean patients did not report postoperative pain. Almost half of the population (47.2%) studied presented side effects with the use of intrathecal morphine, mainly pruritus. 80.5% expressed satisfaction with postoperative analgesia. Conclusions the majority of patients were satisfied with the analgesic treatment, despite the presence of adverse effects, so that the use of intrathecal morphine is effective in the management of post-cesarean section pain.

Study on the Effects of Corilagin on Microglia Activation in the Spinal Cord of Morphine-tolerant Rats / 华中科技大学学报(医学版)

Objective This study was designed to investigate the effects of corilagin on morphine-tolerant rats and discuss the reaction mechanism.Methods A rat model of chronic morphine analgesia tolerance was established.The tail-flick latency of rats was detected by using the water bath tail-flick method.The positive cell rate of ionized calcium binding adapter molecule-1(Iba-1)was detected by using immunofluorescence assay.The protein expressions of Iba-1 and mitogen-activated protein kinase(MAPK)pathway-related proteins were detected by Western blotting.The release of interleukin-6(IL-6),tumor necrosis factor alpha(TNF-α)and interleukin-1 beta(IL-1β)was detected by using enzyme-linked immunosorbent assay(ELISA).The mRNA levels of IL-6,TNF-α and IL-1β were detected by using quantitative reverse transcriptase polymerase chain reaction(qRT-PCR).Results Compared with the morphine(Mor)group,the analgesic effect of morphine in morphine+corilagin(Mor+Cor)group was strengthened with the increase of corilagin concentration.Compared with the Control group,the positive cell rate of Iba-1,Iba-1 protein expression level,levels of inflammatory factors IL-6,TNF-α,IL-1β,and the phosphorylated expression levels of MAPK signaling pathway-related proteins extracellular regulated protein kinases(ERK),c-Jun N-terminal kinase(JNK)and p38 were significantly increased in the Mor group,which were then decreased in Mor+Cor group with the increase of corilagin con-centration.Morphine and corilagin treatment(alone or in combination)had no significant effects on the expression levels of ERK,JNK and p38.Conclusion Corilagin reduces morphine tolerance in rats by inhibiting MAPK pathway.

The regulatory effect of morphine postconditioning in left stellate ganglion on remodeling after myocardial infarction / 中国药理学通报

Aim To investigate the regulatory effect of morphine postconditioning in the LSG on remodeling after myocardial infarction. Methods SD rats were randomly divided into four groups: sham operation group (Sham), myocardial infarction group (MI), myocardial infarction + saline group (Control) and myocardial infarction + morphine postconditioning group (MI + Morphine) . The rat MI model was constructed by ligating the left anterior descending coronary artery, and then morphine was given to the LSG by percutaneous posterior approach. After four weeks, the changes of cardiac function in rats were detected by ultrasound. Masson staining was used to detect fibrosis changes; the expression of Collagen I and Collagen III protein was detected by Western blot. The mRNA expression of ANP and BNP was detected by RT-qPCR. The expression of JJLOR in LSG was detected by immunofluorescence. The concentration of catecholamine in plasma and myocardial tissue was detected by ELISA. Results Compared with the sham group, the cardiac function of the MI group was significantly impaired, the myocardial tissue showed significant fibrosis changes, and the concentration of catecholamine in plasma and myocardial tissue significantly increased. Compared with the control group, the MI + Morphine group reduced myocardial fibrosis collagen deposition in rats after MI, inhibited the expression of ANP and BNP in myocardial tissue, reduced the concentration of catecholamine, and improved the cardiac function of MI rats. Immunofluorescence results showed that JJLOR was expressed in LSG after MI and increased after morphine postconditioning. Conclusions This study shows that morphine postconditioning in the LSG has a protective effect on myocardial remodeling after myocardial infarction. The mechanism may be related to the activation of JJLOR in the LSG by morphine and the reduction of catecholamine release from sympathetic nerve endings.

Glycyrrhizin inhibits the neurotoxic effects and mechanisms induced by morphine / 中国临床药理学与治疗学

AIM:To investigate the regulatory ef-fects and mechanisms of glycyrrhizin on morphine-induced neurotoxicity.METHODS:A neurotoxicity model was established by intracerebroventricular injection of morphine.Glycyrrhizin was adminis-tered intraperitoneally for 5 and 10 days.Pathologi-cal observation,protein immunoblotting,cell viabil-ity,apoptosis,and primary neuron differentiation were assessed.RESULTS:After morphine treat-ment,neuronal loss,decreased cell viability,in-creased apoptosis,axonal breakage,and cell shrink-age were observed in cortical tissue.Glycyrrhizin administration significantly improved cell viability,and axonal,dendritic,and cell body structures gradually became intact,with reduced apoptosis.The phosphorylation levels of protein Akt at posi-tion 473 and PKA at position 197 decreased,while autophagy-related proteins Beclin and LC3B1/2 re-mained unchanged.CONCLUSION:Glycyrrhizin sig-nificantly inhibits morphine-induced neuronal dif-ferentiation suppression and neuronal apoptosis,which may be mediated through the synergistic ef-fects of glycyrrhizin and morphine on the Akt path-way.

Effects of different concentrations of morphine in combination with ropivacaine on proliferation,migration,invasion and cell cycle in MDA-MB-231 breast cancer cells / 中国现代医生

Objective To investigate the effects of different concentrations of morphine in combination with ropivacaine on proliferation,migration,invasion and cell cycle in MDA-MB-231 breast cancer cells.Methods MDA-MB-231 breast cancer cells were inoculated on the culture plate for 24h and randomly divided into 8 groups:Control group(C),ropivacaine 400μg/ml group(R),morphine 3μg/ml group(LM),morphine 30μg/ml group(MM),morphine 300μg/ml group(HM),ropivacaine 400μg/ml group+ morphine 3μg/ml group(R+LM),ropivacaine 400μg/ml+ morphine 30μg/ml group(R+MM),and ropivacaine 400μg/ml+ morphine 300μg/ml group(R+HM).After treaments of MDA-MB-231 breast cancer cells for 24h,these proliferation,migration,invasion and cell cycle were evaluated.Results When using morphine alone,the proliferation inhibitive effect was positively correlated with the concentration of morphine.The proliferation was significantly inhibited by morphine of LM,MM,HM group(P<0.05).When using ropivacaine alone,the proliferation was significantly inhibited(P<0.05).When using morphine combined with ropivacaine,the high concentration morphine group has a synergistic effect with ropivacaine group on proliferation inhibition(P<0.05).When using morphine alone,the migration rate decreases sequentially with the increase of morphine concentration.The migration rate was significantly inhibited by morphine of LM,MM,HM group(P<0.05).When using ropivacaine alone,the migration rate was inhibited(P<0.05).When using morphine combined with ropivacaine,the low and medium concentration morphine group have a synergistic effect with ropivacaine group on migration rate(P<0.05).When using morphine alone,the number of cell invasion was decreased with the concentration of morphine increasing(P<0.05).The MM and HM groups inhibited cell invasion ability.When using ropivacaine alone,the invasiveness of cells was also inhibited(P<0.05).When using morphine combined with ropivacaine,the medium and high concentration morphine groups have a synergistic effect with ropivacaine group on inhibiting cell invasion ability(P<0.05).When using morphine alone,the cell cycle progression was inhibited into G2/M Phase(P<0.05).When using ropivacaine alone,the cell cycle progression was inhibited into G2/M phase(P<0.05).The combination of low concentration morphine and ropivacaine has synergistic effect on arresting at G0/G1 and S phase(P<0.05).Conclusion Morphine combined with ropivacaine inhibits the Proliferation,migration and invasion of MDA-MB-231 breast cancer cells in a dose-dependent manner.

Bomba de infusión intratecal programable de morfina en paciente con dolor oncológico refractario / Programmable intrathecal morphine infusion pump in a patient with refractory oncological pain / Bomba de infusão intratecal programável de morfina em paciente com dor oncológica refratária

El control del dolor es uno de los desafíos más importantes en el ámbito de cuidados paliativos y tiene un profundo impacto en la calidad de vida de los pacientes. En la mayoría de los casos, el dolor crónico oncológico severo puede ser controlado con opioides; sin embargo, hay una población de pacientes, estimada entre 10 a 20%, que experimenta dolor refractario que requiere abordajes más complejos. En pacientes con dolor intratable o efectos adversos intolerables, la terapia basada en la infusión intratecal de opioides debe ser considerada como parte de la estrategia terapéutica. Presentamos el caso de una paciente con un tumor maligno de mediastino anterior con dolor refractario a pesar de altas dosis de opioides y coadyuvantes. Dada la refractariedad del síntoma, se decide colocar bomba intratecal de morfina para disminuir dosis de opioides y optimizar analgesia. La dosis inicial se titula progresivamente en respuesta al reporte de la paciente y la evaluación clínica. La paciente falleció tranquila y sin dolor, con una dosis de morfina intratecal de 4500 µg/día. Se concluye que la administración intratecal de analgésicos opioides mediante el implante de dispositivos programables de infusión continua para pacientes con dolor oncológico refractario es una estrategia efectiva y segura, basada en la evidencia, que permite optimizar la analgesia cuando otras técnicas han fallado.

Pain control is one of the most important challenges in the field of palliative care and has a profound impact on patients' quality of life. In most cases, severe oncological chronic pain can be managed with opioids; however, there is a population of patients, estimated to be between 10% and 20%, who experience refractory pain that requires more complex approaches. In patients with intractable pain or intolerable adverse effects, therapy based on intrathecal opioid infusion should be considered as part of the therapeutic strategy. We present the case of a patient with a malignant tumor in the anterior mediastinum who had refractory pain despite high doses of opioids and adjuvants. Given the refractory nature of the symptom, it was decided to place an intrathecal morphine pump to reduce opioid doses and optimize analgesia. The initial dose is titrated progressively in response to the patient's reports and clinical evaluation. The patient passed away peacefully and painlessly, with an intrathecal morphine dose of 4500 µg/day. It is concluded that the intrathecal administration of opioid analgesics through the implantation of programmable continuous infusion devices for patients with refractory oncological pain is an effective and safe strategy, based on evidence, that allows for the optimization of analgesia when other techniques have failed.

O controle da dor é um dos desafios mais importantes no campo dos cuidados paliativos e tem um profundo impacto na qualidade de vida dos pacientes. Na maioria dos casos, a dor crônica oncológica severa pode ser controlada com opioides; no entanto, há uma população de pacientes, estimada entre 10% e 20%, que experimenta dor refratária e requer abordagens mais complexas. Em pacientes com dor intratável ou efeitos adversos intoleráveis, a terapia baseada na infusão intratecal de opioides deve ser considerada como parte da estratégia terapêutica. Apresentamos o caso de uma paciente com um tumor maligno no mediastino anterior que apresentava dor refratária, apesar de altas doses de opioides e coadjuvantes. Dada a refratariedade do sintoma, decidiu-se implantar uma bomba intratecal de morfina para reduzir as doses de opioides e otimizar a analgesia. A dose inicial é titulada progressivamente em resposta aos relatos da paciente e à avaliação clínica. A paciente faleceu tranquila e sem dor, com uma dose de morfina intratecal de 4500 µg/dia. Conclui-se que a administração intratecal de analgésicos opioides por meio do implante de dispositivos programáveis de infusão contínua para pacientes com dor oncológica refratária é uma estratégia eficaz e segura, baseada em evidências, que permite otimizar a analgesia quando outras técnicas falharam.

The effects of drainage tube on pain and functional recovery after unicompartmental knee arthroplasty / Efeitos do tubo de drenagem na dor e recuperação funcional após artroplastia unicompartimental do joelho

ABSTRACT Objective: The objective of this study was to evaluate the impact of drainage tube placement on postoperative pain, recovery, and opioid consumption within a 72-hour period following unicompartmental knee arthroplasty (UKA). Methods: Patients with medial knee osteoarthritis who underwent UKA from January 2019 to August 2020 were enrolled in the study and divided into two groups based on whether they received a drain postoperatively. Results: The drainage group had significantly lower VAS scores on day 1, day 2, and day 3, in addition to significantly smaller changes in the circumference of the knee joint within 3 days postoperatively (P <0.05). The ROM in the drainage group significantly increased at 3 days and 1 month post-surgery, with a statistically significant difference in morphine consumption between the two groups at 3 days (P<0.05). The incidence of postoperative nausea and vomiting (5 cases) and wound bleeding (1 case) was lower in the drainage group compared to the non-drainage group (P<0.05). Conclusions: The placement of a drainage tube in UKA may reduce the swelling of knee joint and pain, which not only reduces the use of Opioid but also facilitates early functional activities of the knee joint. Level of Evidence III; Retrospective Comparative Study.

RESUMO Objetivo: O objetivo deste estudo foi avaliar o impacto da implantação do tubo de drenagem na dor pós-operatória, na recuperação e no consumo de opioides em um período de 72 horas após a artroplastia unicompartimental do joelho (UKA). Métodos: Pacientes com osteoartrite medial do joelho submetidos à UKA de janeiro de 2019 a agosto de 2020 foram incluídos no estudo e divididos em dois grupos com base no fato de terem ou não recebido um dreno no pós-operatório. Resultados: O grupo de drenagem apresentou escores EVA significativamente menores no dia 1, no dia 2 e no dia 3, além de alterações significativamente menores na circunferência da articulação do joelho em 3 dias de pós-operatório (P <0,05). A ADM no grupo de drenagem aumentou significativamente em 3 dias e 1 mês após a cirurgia, com uma diferença estatisticamente significativa no consumo de morfina entre os dois grupos em 3 dias (P<0,05). A incidência de náuseas e vômitos no pós-operatório(5 casos) e sangramento da ferida (1 caso) foi menor no grupo de drenagem em comparação com o grupo sem drenagem (P<0,05). Conclusão: A utilização de tubo de drenagem na UKA pode reduzir o edema articular do joelho e a dor, reduzindo o uso de opioides e facilitando as atividades funcionais iniciais da articulação do joelho. Nível de Evidência III; Estudo Comparativo Retrospectivo.

Morfina/ketamina versus morfina en el control del dolor postoperatorio de cirugía renal electiva / Morphine/ketamine versus morphine in postoperative pain control for elective renal surgery

Resumen: Introducción: el dolor agudo postoperatorio demora la recuperación funcional del paciente. Objetivo: evaluar utilidad de la ketamina asociada a morfina administrados en bolos intravenosos en el control del dolor agudo postoperatorio de pacientes sometidos a cirugía renal electiva. Material y métodos: realizamos estudio doble ciego en pacientes con dolor postoperatorio moderado-severo sometidos a cirugía renal electiva. Se conformaron dos grupos: grupo MK administramos morfina 0.05 mg/kg más ketamina 0.2 mg/kg y grupo M morfina 0.05 mg/kg más solución salina a 0.9%. Pacientes con dolor de intensidad moderada-severa según escala analógica visual recibieron dosis de morfina cada 20 minutos hasta lograr dolor ligero, registrándose el consumo total de morfina por paciente. La tensión arterial, frecuencia cardíaca y respiratoria, saturación de oxígeno y efectos adversos fueron evaluados con la misma periodicidad. Resultados: el grupo MK mostró menor intensidad del dolor con disminución significativa del consumo de morfina. Ambos grupos resultaron ser similares en cuanto a cifras de tensión arterial, frecuencia cardíaca, frecuencia respiratoria y saturación de oxígeno. Las náuseas y vómitos fueron los efectos adversos de mayor prevalencia, siendo superiores en el grupo morfina. Conclusiones: la asociación morfina-ketamina resultó útil en el control del dolor moderado-severo en pacientes sometidos a cirugía renal electiva.

Abstract: Introduction: acute postoperative pain delays the patient's functional recovery. Objective: to evaluate the utility of ketamine associated with morphine administered in intravenous boluses in the control of acute postoperative pain in patients undergoing elective renal surgery. Material and methods: we conducted a double-blind study in patients with moderate-severe postoperative pain undergoing elective renal surgery. Two groups were formed: group MK administered 0.05 mg/kg morphine plus 0.2 mg/kg ketamine and group M 0.05 mg/kg morphine plus 0.9% saline solution. Patients with pain of moderate-severe intensity according to the visual analogue scale received doses of morphine every 20 minutes until achieving light pain, recording the total consumption of morphine per patient. Blood pressure, heart and respiratory rates, oxygen saturation, and adverse effects were evaluated with the same periodicity. Results: MK group showed lower pain intensity with a significant decrease in morphine consumption. Both groups turned out to be similar in terms of blood pressure, heart rate, respiratory rate and oxygen saturation Figures. Nausea and vomiting were the most prevalent adverse effects, being higher in the morphine group. Conclusions: the morphine-ketamine association was useful in the control of moderate-severe pain in patients undergoing elective renal surgery.

Sospecha de hipersensibilidad probablemente relacionada con el uso de morfina: reporte de caso / Suspected hypersensitivity probably related to the use of morphine: A case report

RESUMEN Se presenta el caso de un paciente masculino de 46 años. Este ingresó al servicio de urgencias con un cuadro clínico de una hora de evolución caracterizado por dolor torácico opresivo de intensidad 10/10 según la escala análoga del dolor. Después de la valoración y frente a los hallazgos electrocardiográficos y de laboratorio, se diagnosticó al paciente con infarto agudo de miocardio con elevación del ST, además, se sospechó de disección aórtica y de una emergencia hipertensiva a órgano blanco corazón debido al intenso dolor precordial y las cifras tensionales de 230/120 mmHg. Dentro del esquema terapéutico, se indicaron 3 mg de morfina intravenosa diluida en 10 ml de solución salina 0,9%. Después de la administración, el paciente presentó sospecha de hipersensibilidad. Por ende, se realizó una evaluación de sospecha de evento adverso utilizando el algoritmo de Naranjo y se estableció que los efectos de morfina eran plausibles (categoría probable).

ABSTRACT The case of a 46-year-old male patient is presented. He was admitted to the emergency department with a clinical picture of oppressive chest pain of 10/10 intensity on the pain analog scale, which had been evolving for one hour. After evaluation and based on electrocardiographic and laboratory findings, the patient was diagnosed with acute myocardial infarction with st elevation. Additionally, aortic dissection and hypertensive emergency with end-organ damage to the heart were suspected due to intense precordial pain and blood pressure readings of 230/120 mmHg. As part of the therapeutic approach, 3 mg of intravenous morphine diluted in 10 ml of 0.9 % saline solution were administered. Following administration, the patient exhibited suspected hypersensitivity. Therefore, a suspected adverse event assessment was performed using the Naranjo algorithm, and it was established that the effects of morphine were plausible (category probable).

Comparison of two analysis methods of opioid consumption sum in medical institutions / 中国药房

OBJECTIVE To compare the similarities and differences of the two methods in analyzing the use of opioids in third grade class A medical institutions and provide a reference for the management of opioids in medical institutions. METHODS Two methods， Defined Daily Dose （DDD） and Oral Morphine Equivalent （OME）， were used to count the opioid prescription data of five comprehensive medical institutions of third grade class A （named H1-H5） in Shanxi province in 2020， calculate consumption sum of opioid， annual per capita consumption sum， patient cost burden and drug consumption sum ratio， compare the index results presented by the two analysis methods， and explore the application scenarios of the advantages of each of the two evaluation methods. RESULTS The ranking of consumption sum of opioid and patient cost burden calculated by the two methods was the same in the five sample medical institutions， but the ranking of per capita consumption sum was different. Taking the 5 medical institutions as a whole， the top 4 rankings of consumption sum ratio for each species of opioid compared by both methods were the same， i. e. remifentanil＞sufentanil＞oxycodone＞morphine. The ratio of remifentanil was close to 50%. When comparing the ranking of consumption sum ratio in each medical institution， the ranking calculated by the two methods was different for those medical institutions except for H1 medical institutions. The consumption sum ratio of fentanyl calculated by DDD method was significantly higher than that of OME method； whereas consumption sum ratio of remifentanil calculated by OME method was significantly higher than that of DDD method. Perioperative patients had the highest consumption sum ratio， about 50%. The consumption sum ratio of critically ill patients in H3 jwsydey@163.com medical institutions and inpatient patients with cancer pain and other patients in H5 medical institutions calculated by DDD method was significantly higher than that by OME method. There were differences in the order of cost burden of different types of patients calculated by two methods. CONCLUSIONS DDD method can accurately reflect the dosage of opioid drugs and facilitate the monitoring and management of the dosage； OME method can more reflect the analgesic effect and compare the cost burden of patients.

Refractory Diarrhea Associated with Carcinoid Syndrome Improved after Opioid Switching from Fentanyl to Morphine

Background: In the case of refractory diarrhea that cannot be treated with loperamide only, drugs such as octreotide and serotonin receptor antagonists are generally recommended. We have reported a case of refractory diarrhea associated with carcinoid syndrome in which symptoms improved only with opioid switching, without octreotide. Case: We experienced a case of a 28-year-old female with cervical cancer. She was diagnosed with recurrence after cervical cancer surgery and presented with pain and diarrhea. Her diarrhea did not improve sufficiently after taking loperamide. She was admitted to the palliative care hospital for symptom control due to persistent diarrhea and right lower extremity pain associated with bone metastasis. We diagnosed the cause of her diarrhea as carcinoid syndrome by some laboratory examination. For pain management, we switched opioids from transdermal fentanyl to continuous subcutaneous infusion of morphine. It resulted in pain relief and improvement in the frequency of diarrhea, and she was able to be discharged home. Conclusion: In cases of refractory diarrhea and in patients who need opioids, there is one option to use morphine. If it is effective, it may simply resolve both pain and diarrhea and reduce the use of multiple medications.

Role of autophagy in morphine preconditioning-induced reduction of OGD/R injury in primary cortical neurons of mice and the relationship with JNK / 中华麻醉学杂志

Objective:To evaluate the role of autophagy in morphine preconditioning-induced reduction of oxygen-glucose deprivation and restoration (OGD/R) injury in primary cortical neurons of mice and the relationship with c-Jun N-terminal kinase (JNK).Methods:Primary cortical neurons extracted from C57BL/6 neonatal mice within 24 h after birth were divided into 9 groups ( n=24 each) using a random number table method: control group (C group), OGD/R group, morphine preconditioning group (M group), autophagy inhibitor 3-methyladenine (3-MA) group (3-MA group), 3-MA+ morphine preconditioning group (3-MA+ M group), autophagy inhibitor chloroquine group (Ch group), chloroquine + morphine preconditioning group (Ch+ M group), JNK inhibitor SP600125 group (SP group) and SP600125 + morphine preconditioning group (SP+ M group). Morphine preconditioning: morphine was added at a final concentration of 3 μmol/L before OGD/R, and the cells were incubated for 2 h in OGD/R group. In 3-MA, Ch and SP groups, 3-MA 5 mmol/L, chloroquine 50 μmol/L and SP600125 25 μmol/L were added, respectively, and the cells were incubated for 150 min. In 3-MA+ M, Ch+ M and SP+ M groups, 3-MA 5 mmol/L, chloroquine 50 μmol/L and SP600125 25 μmol/L were added, respectively, at 30 min before morphine preconditioning. Then the cells were subjected to oxygen-glucose deprivation for 1 h followed by restoration of oxygen-glucose supply for 24 h. CCK-8 assay was used to detect the neuronal viability. The expression of JNK, phosphorylated JNK (p-JNK), microtubule-associated protein 1 light chain 3 (LC3), p62, Beclin1, caspase-3, and cleaved-caspase-3 was determined by Western blot. The autophagosomes and autolysosomes were counted using LC3-double fluorescent adenovirus transfection, and the neuronal apoptosis rate was determined by TUNEL staining. Results:Compared with C group, the neuronal viability was significantly decreased, the expression of Beclin1 was up-regulated, the expression of p62 was down-regulated, and the LC3Ⅱ/LC3Ⅰ ratio, p-JNK/JNK ratio, the number of autophagosomes and autolysosomes, cleaved-caspase-3/caspase-3 ratio and neuronal apoptosis rate were increased in OGD/R group ( P<0.001). Compared with OGD/R group, the neuronal viability, p-JNK/JNK ratio, LC3Ⅱ/LC3Ⅰ ratio and the number of autophagosomes and autolysosomes were significantly increased, the expression of Beclin1 was up-regulated, and the expression of p62 was down-regulated in M group, the LC3Ⅱ/LC3Ⅰ ratio was significantly decreased, and the expression of p62 was down-regulated in 3-MA group, the LC3Ⅱ/LC3Ⅰ ratio was significantly increased, and the expression of p62 was up-regulated in Ch group ( P<0.001), and no significant change was found in the parameters mentioned above in SP600125 group ( P>0.05). Compared with M group, the neuronal viability was significantly decreased, the LC3Ⅱ/LC3Ⅰ ratio was decreased, and the expression of p62 was up-regulated in M+ 3-MA group, the neuronal viability was significantly decreased, the LC3Ⅱ/LC3Ⅰ ratio was increased, and the expression of p62 was up-regulated in M+ Ch group, and the neuronal viability, LC3Ⅱ/LC3Ⅰ ratio and p-JNK/JNK ratio were significantly decreased, the expression of p62 was up-regulated, the number of autophagosomes and autolysosomes was decreased, the expression of Beclin1 was down-regulated, and the cleaved-caspase-3/caspase-3 ratio and neuronal apoptosis rate were increased in M+ SP group ( P<0.001). Conclusions:Morphine preconditioning can attenuate OGD/R injury by activating JNK, enhancing autophagy and inhibiting apoptosis in primary cortical neurons of mice.

Effect of berberine on morphine-induced activation of BV2 microglial cells / 中华麻醉学杂志

Objective:To evaluate the effect of berberine (BBR) on morphine-induced activation of BV2 microglial cells.Methods:The BV2 microglial cells were divided into 3 groups ( n=12 each) using a random number table method: control group (C group), morphine group (Mor group)and morphine+ BBR group (Mor+ BBR group). The Mor group was treated for 24 h with a final concentration of 200 μmol/L morphine, while C group was treated for 24 h with an equal volume of PBS buffer. Mor+ BBR group was first treated for 2 h with a final concentration of 20 μmol/L berberine, followed by treatment with a final concentration of 200 μmol/L morphine for another 24 h. The viability of BV2 microglial cells was determined using the CCK-8 assay, the concentrations of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and IL-10 in supernatant were measured using enzyme-linked immunosorbent assay, and the expression of CD86 and NF-κB proteins in microglial cells was detected using Western blot. Results:Compared with group C, the BV2 microglial cell viability and concentrations of IL-1β and TNF-α were significantly increased, the concentrations of IL-10 were decreased, and the expression of CD86 and NF-κB in microglial cells was up-regulated in Mor group ( P<0.05). Compared with Mor group, the BV2 microglial cell viability and concentrations of IL-1β and TNF-α were significantly decreased, the concentrations of IL-10 were increased, and the expression of CD86 and NF-κB in microglial cells was down-regulated in Mor+ BBR group( P<0.05). Conclusions:BBR can inhibit morphine-induced activation of BV2 microglial cells.

Role of circTmeff-1 in morphine addiction memory of mice / 中国药理学与毒理学杂志

In addition to the essential pharmacologi-cal effects of opioids,situational cues associated with drug addiction memory are key triggers for drug seeking.CircRNAs,an emerging hotspot regulator in crown genet-ics-play an important role in central nervous system-relat-ed diseases.However,the internal mediating mechanism of circRNA in the field of drug reward and addiction mem-ory remains unknown.Here,we trained mice on a condi-tional place preference(CPP)model and collected nucle-us accumbens(NAc)tissues from day 1(T0)and day 8(T1)for high-throughput RNA sequencing.qRT-PCR revealed that circTmeff-1 was highly expressed in the NAc core but not in the NAc shell,suggesting that it plays a role in addiction memory formation.Meanwhile,the reverse regulation of circTmeff-1 by adeno-associated viruses could both inhibit the formation of addiction mem-ory in the NAc core or shell.Subsequently,the GO and KEGG analyses indicated 21 that circTmeff-1 might regu-late the addiction memory via the MAPK and AMPK path-ways.These findings suggest that circTmeff-1 in NAc plays a crucial role in morphine-dependent memory for-mation.

Effects of SIRT1 on morphine-induced conditioned place preference in rats through CREB/BDNF pathway / 中国药理学通报

Aim To investigate the effect of microinjection of EX527, a selective SIRT1 antagonist, into the ventrolateral orbital cortex (VLO) on morphine-induced conditioned place preference (CPP), and to explore the role of CREB/BDNF in it. Methods The cannulas were implanted bilaterally in the VLO of rats by brain stereotaxis surgery, and the model of morphine-induced CPP was established. The behavioral experiment consisted of four stages:habituation (d 1), pre-test (d 2-4), conditioning training (d 5-14) and test (d 15). At the stage of conditioning training, EX527 (1 μL, 5 g·L

Targeting Peripheral μ-opioid Receptors or μ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance / 神经科学通报·英文版

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity (OIH) and analgesic tolerance. Among the different forms of OIH and tolerance, the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved. Here we demonstrated that the loss of peripheral μ-opioid receptors (MORs) or MOR-expressing neurons attenuated thermal tolerance, but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance. To confirm this result, we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons. Consistent with the behavioral results, peripheral MOR loss did not prevent the opening of Aβ mechanical allodynia pathways in the spinal dorsal horn. Therefore, the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance. Future studies should focus more on central mechanisms.

Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis / 药物分析学报

Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/β-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knock-down.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/β-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alle-viated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/β-arrestin2 pathway.Collectively,our study provided a therapeutic mAb,3A5C7,targeting MOR to treat morphine tolerance,mediated by enhancing morphine-induced MOR endocytosis.The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.

Analysis of constipation status and influencing factors in patients with lung cancer during postoperative hospitalization / 中国胸心血管外科临床杂志

@#Objective     To investigate the current status of constipation during postoperative hospitalization and the factors associated with moderate to severe constipation at discharge in lung cancer patients. Methods     Lung cancer patients who underwent surgery in 6 tertiary hospitals in Sichuan Province from November 2017 to January 2020 were enrolled. The MD Anderson Symptom Scale-Lung Cancer Module was used to collect postoperative constipation scores. Unconditional logistic stepwise regression was used to analyze the related influencing factors for moderate to severe constipation on the day of discharge. Results     Finally 337 patients were collected. There were 171 males and 166 females, with an average age of 55.0±10.3 years. Constipation scores of lung cancer patients increased from postoperative day 1 to day 3, and showed a decreasing trend from day 3 to day 7. Moderate to severe constipation was present in 68 (20.2%) patients at discharge. The postoperative hospital stay (OR=0.743, P<0.001) and the dose of morphine used during postoperative hospitalization (OR=1.002, P=0.015) were influencing factors for moderate to severe constipation at discharge in lung cancer patients. Conclusion    Lung cancer patients have the most severe constipation on postoperative day 3. Moderate to severe constipation at discharge is associated with the postoperative hospital stay and the dose of morphine used during postoperative hospitalization.

Morphine promotes migration and lung metastasis of mouse melanoma cells

Abstract Background Morphine is an analgesic agent used for cancer pain management. There have been recent concerns that the immunosuppressant properties of morphine can also promote cancer metastasis. Morphine is an agonist for toll like receptor 4 (TLR4) that has a dual role in cancer development. The promotor or inhibitor role of morphine in cancer progression remains controversial. We investigated the effects of morphine on migration and metastasis of melanoma cells through TLR4 activation. Methods Mouse melanoma cells (B16F10) were treated with only morphine (0, 0.1, 1, and 10 μM) or in combination with a TLR4 inhibitor (morphine10 μM +CLI-095 1μM) for either 12 or 24 hours. Migration of cells was analyzed by transwell migration assays. Twenty C57BL/6 male mice were inoculated with B16F10 cells via the left ventricle of the heart and then randomly divided into two groups (n = 10 each) that received either morphine (10 mg.kg−1, sub-q) or PBS injection for 21 days (control group). Animals were euthanized and their lungs removed for evaluation of metastatic nodules. Results Morphine (0.1, 1, and 10 μM) increased cell migration after 12 hours (p < 0.001) and after 24 hours of treatment with morphine (10 μM) (p < 0.001). Treatment with CLI-095 suppressed migration compared to cells treated with morphine alone (p < 0.001). Metastatic nodules in the morphine-treated group (64 nodules) were significantly higher than in the control group (40 nodules) (p < 0.05). Conclusion Morphine increases the migration and metastasis of mouse melanoma cells by activating TLR4.