Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38.605
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-36244467

RESUMO

Embryonic morphine exposure (EME) leads to abnormal brain development and behavior in the offspring, and the functional alteration of γ-aminobutyric acid (GABA) system is considered to be one of the important mechanisms. To mimic the problem of susceptibility of human gestational drug abuse on addictive drugs in offspring, we administered morphine exposure on days 5-8 and 13-16 of chicken embryo development and examined the functions of GABA neurons and their receptors in postnatal chicks by neuroelectrophysiology, immunohistochemistry and behavioral methods. We found that morphine exposure during embryonic stages 5-8 (MorphineE5-8) significantly reduced the incidence of spontaneous inhibitory postsynaptic potentiation (IPSP) and the induction of evoked IPSP and the mean amplitude of GABAA agonist muscimol-induced response in the intermediate medial interstitial (IMM) region, compared to naïve controls or saline-exposed chicks. The results of immunocytochemistry further suggest that MorphineE5-8 decreased the synaptic density of GAD-expressing sites in the IMM, while increased the expression of the GABAA receptor subtype γ2 isoform. Behavioral results found that Morphine5-8 treatment de-inhibited morphine-induced psychomotor responses in postnatal chicks. Morphine exposure at embryonic stages 13-16 (MorphineE13-16) showed no significant changes in the above indicators compared to the saline group. Evidence suggests that early embryonic morphine exposure leads to defects in GABAergic function in the IMM, which in turn alters the responsiveness of postnatal chicks to addictive drugs. These results will help to understand the GABA mechanisms by which embryonic addictive drug exposure contributes to offspring susceptibility to addiction.


Assuntos
Galinhas , Morfina , Humanos , Animais , Embrião de Galinha , Morfina/farmacologia , Galinhas/metabolismo , Ácido gama-Aminobutírico/metabolismo , Encéfalo/metabolismo , Neurônios , Receptores de GABA-A/metabolismo
2.
Synapse ; 77(1): e22256, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36200789

RESUMO

The basolateral amygdala (BLA), which is sensitive to stress, is necessary for reward-seeking behavior and addiction. Regular exercise can produce various positive effects by affecting the BLA. Therefore, we aimed to investigate the effects of chronic stress and treadmill running (TR) on anxiety-like behavior, neuronal activity, lipid peroxidation (measured by malondialdehyde (MDA) levels, a marker for oxidative stress), and total thiol in BLA, in morphine-treated rats. Male Wistar rats were restricted in restraint stress and/or ran on the treadmill and treated with morphine (5 mg/kg) for 21 days. Anxiety-like behavior was evaluated using an elevated plus maze (EPM) and open field tests (OFTs), on day 22. On day 23, neuronal activity in BLA was assessed via single-unit recording. Finally, MDA and total thiol were assessed in BLA. Our results showed that chronic administration of morphine (5 mg/kg) did not affect anxiety-like behavior. However, the morphine-treated rats, subjected to chronic stress and exercise, showed fewer anxiety-like behaviors. Morphine increased BLA's MDA levels but it was prevented by TR. Glutamatergic and GABAergic basal neuronal activities were low in morphine-treated rats but after acute morphine application, there was a significant decrease in GABAergic neuronal activities in the morphine-exercise-stress (Mor-Exe-St) group. The results of this study showed that in morphine-treated rats, stress and exercise or their combination could have either co-directional or opposite effects to the chronic effects of morphine. These results indicate the existence of common pathways similar to endogenous opioids.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Ratos , Masculino , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Morfina/farmacologia , Ratos Wistar , Ansiedade , Estresse Oxidativo , Compostos de Sulfidrila/metabolismo , Compostos de Sulfidrila/farmacologia
3.
Adv Wound Care (New Rochelle) ; 12(1): 1-14, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35081741

RESUMO

Objective: Although the use of dexamethasone as an adjunct agent is associated with alleviating pain and prolonging analgesic duration in local wound infiltration (LWI), efficacy and safety of dexamethasone infiltration have not been fully explored. The study sought to quantify the pooled effects of dexamethasone infiltration on postoperative pain, analgesic consumption, and side effects through a review of randomized controlled trials (RCTs). Approach: RCTs comparing dexamethasone + LWI with LWI alone were retrieved from seven electronic databases. Co-primary outcomes were rest pain scores and cumulative morphine equivalent consumption within 24 h postoperatively. The study followed PRISMA, AMSTAR, and the Cochrane Collaboration. Results: Eight trials comprising 609 patients were included in the final analysis. Results indicated that dexamethasone infiltration effects were only statistical but not clinically significant at individual time points of rest pain and patient satisfaction scores. Notably, the effect of dexamethasone infiltration therapy on other pain-related parameters, including cumulative morphine consumption (mean difference, -9.05 mg; 95% CI: -22.47 to 4.37), was not significantly different compared with the control group. Analysis showed no significant differences in safety indicators between the two groups. The overall quality of evidence was high to very low. Innovation: Although statistically significant effects of dexamethasone infiltration were observed for some outcomes of postoperative wound pain, the overall benefits were below the expected minimal clinically important difference. Conclusions: In summary, the current evidence does not support routine clinical use of dexamethasone in LWI. However, further studies should explore the clinical value of preemptive analgesia and safety of a combination of dexamethasone with ropivacaine for LWI.


Assuntos
Analgesia , Dor Pós-Operatória , Humanos , Ropivacaina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Morfina/farmacologia , Morfina/uso terapêutico , Analgesia/métodos , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Behav Brain Res ; 437: 114122, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36174840

RESUMO

Gender differences have been observed in the vulnerability to drug abuse and in the different stages of the addictive process. In opiate dependence, differences between sexes have been shown in humans and laboratory animals in various phases of opiate addiction, especially in withdrawal-associated negative affective states. Using a Y-maze conditioned place aversion paradigm, we investigated potential sex differences in the expression and extinction of the aversive memory of precipitated opiate withdrawal state in morphine-dependent rats. No significant difference between sexes was observed in the occurrence of withdrawal signs following naloxone injection during conditioning. Moreover, opiate withdrawal memory expression and extinction following repeated testing was demonstrated in both male and female rats, with no significant differences between sexes. Finally, we report spontaneous recovery following extinction of opiate withdrawal memory. Altogether these data provide further evidence that persistent withdrawal-related memories may be strong drivers of opiate dependence, and demonstrate that both males and females can be used in experimental rodent cohorts to better understand opiate-related effects, reward, aversive state of withdrawal, abstinence and relapse.


Assuntos
Dependência de Morfina , Alcaloides Opiáceos , Transtornos Relacionados ao Uso de Opioides , Síndrome de Abstinência a Substâncias , Humanos , Ratos , Animais , Feminino , Masculino , Síndrome de Abstinência a Substâncias/metabolismo , Aprendizagem da Esquiva , Naloxona/farmacologia , Analgésicos Opioides/farmacologia , Dependência de Morfina/metabolismo , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia
5.
Behav Brain Res ; 437: 114159, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36241071

RESUMO

It has been shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) prevents morphine-induced conditioned place preference (CPP) in rats. However, our previous study demonstrated that the application of DBS at 150 µA did not block morphine CPP in all rats. Here, we investigated the possibility to completely block morphine CPP by increasing the intensity of LH DBS. Morphine reward was assessed by the CPP paradigm in male Wistar rats. DBS was applied in the LH during the conditioning trials with morphine (5 mg/kg, S.C.) at 130 Hz pulse frequency, 100 µs pulse duration, and either 150 µA or 200 µA pulse amplitude. Results showed that repeated morphine injections produced a robust CPP that was blocked partially by DBS at 150 µA and completely by DBS at 200 µA. Response rate was 47% with 150-µA and 100% with 200-µA stimulation. DBS treatment was not associated with changes in motor activity. In conclusion, the development of morphine reward was modulated by LH DBS in an intensity-dependent manner.


Assuntos
Estimulação Encefálica Profunda , Região Hipotalâmica Lateral , Masculino , Animais , Ratos , Região Hipotalâmica Lateral/fisiologia , Morfina/farmacologia , Estimulação Encefálica Profunda/métodos , Ratos Wistar , Recompensa
6.
Reg Anesth Pain Med ; 48(1): 29-36, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36167478

RESUMO

INTRODUCTION: Regional techniques are a key component of multimodal analgesia and help decrease opioid use perioperatively, but some techniques may not be suitable for all patients, such as those with spina bifida. We hypothesized peripheral regional catheters would reduce postoperative opioid use compared with no regional analgesia without increasing pain scores in pediatric patients with spina bifida undergoing major urological surgery. METHODS: A retrospective review of a multicenter database established for the study of enhanced recovery after surgery was performed of patients from 2009 to 2021 who underwent bladder augmentation or creation of catheterizable channels. Patients without spina bifida and those receiving epidural analgesia were excluded. Opioids were converted into morphine equivalents and normalized to patient weight. RESULTS: 158 patients with pediatric spina bifida from 7 centers were included, including 87 with and 71 without regional catheters. There were no differences in baseline patient factors. Anesthesia setup increased from median 40 min (IQR 34-51) for no regional to 64 min (IQR 40-97) for regional catheters (p<0.01). The regional catheter group had lower median intraoperative opioid usage (0.24 vs 0.80 mg/kg morphine equivalents, p<0.01) as well as lower in-hospital postoperative opioid usage (0.05 vs 0.23 mg/kg/day morphine equivalents, p<0.01). Pain scores were not higher in the regional catheters group. DISCUSSION: Continuous regional analgesia following major urological surgery in children with spina bifida was associated with a 70% intraoperative and 78% postoperative reduction in opioids without higher pain scores. This approach should be considered for similar surgical interventions in this population. TRIAL REGISTRATION NUMBER: NCT03245242.


Assuntos
Analgesia Epidural , Disrafismo Espinal , Humanos , Criança , Analgésicos Opioides , Estudos Retrospectivos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Morfina , Disrafismo Espinal/diagnóstico , Disrafismo Espinal/cirurgia , Disrafismo Espinal/complicações , Estudos Observacionais como Assunto , Estudos Multicêntricos como Assunto
7.
Reg Anesth Pain Med ; 48(1): 1-6, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36261261

RESUMO

INTRODUCTION: Interscalene brachial plexus blocks are a commonly performed procedure to reduce pain following total shoulder arthroplasty. Liposomal bupivacaine has been purported to prolong the duration of brachial plexus blocks for up to 72 hours; however, there has been controversy surrounding the analgesic benefits of this drug. Our hypothesis was that an interscalene block performed with bupivacaine alone would be non-inferior to a combination of liposomal bupivacaine and bupivacaine with respect to opioid consumption following total shoulder arthroplasty. METHODS: Subjects presenting for primary total shoulder arthroplasty were randomized in a 1:1 ratio to an ultrasound-guided, single-injection interscalene block with either a combination of liposomal bupivacaine and bupivacaine (LB group) or bupivacaine without additive (Bupi group). The primary outcome of this study was 72-hour postoperative cumulative opioid consumption (in oral morphine equivalents) with a non-inferiority margin of 22.5 mg. Secondary outcomes included pain scores, patient satisfaction with analgesia and patient reported duration of sensory block. RESULTS: Seventy-six subjects, 38 from the Bupi group and 38 from the LB group, completed the study. Analysis of the primary outcome showed a 72-hour cumulative geometric mean oral morphine equivalent consumption difference of 11.9 mg (95% CI -6.9 to 30.8) between groups (calculated on the log scale). This difference constitutes approximately 1.5 tablets of oxycodone over 3 days. No secondary outcomes showed meaningful differences between groups. DISCUSSION: Interscalene brachial plexus blocks performed with bupivacaine alone did not demonstrate non-inferiority compared to a mixture of liposomal bupivacaine plus bupivacaine with regards to 72-hour cumulative opioid consumption following total shoulder arthroplasty. However, the difference between groups did not appear to be clinically meaningful.


Assuntos
Artroplastia do Ombro , Bloqueio do Plexo Braquial , Humanos , Bupivacaína/efeitos adversos , Bloqueio do Plexo Braquial/efeitos adversos , Bloqueio do Plexo Braquial/métodos , Artroplastia do Ombro/efeitos adversos , Analgésicos Opioides , Anestésicos Locais/efeitos adversos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Medição da Dor , Morfina
8.
J Int Med Res ; 50(11): 3000605221138487, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36408532

RESUMO

OBJECTIVE: During March 2020 in the United States, demand for sedatives increased by 91%, that for analgesics rose by 79%, and demand for neuromuscular blockers increased by 105%, all owing to the number of COVID-19 cases requiring invasive mechanical ventilation (MV). We hypothesize that analgesic and sedative requirements decrease following tracheotomy in this patient population. METHODS: In this cross-sectional study, we conducted a retrospective chart review to identify patients with COVID-19 who underwent tracheotomy (T) at an academic medical center between March 2020 and January 2021. We used a paired Student t-test to compare total oral morphine equivalents (OMEs), total lorazepam equivalents, 24-hour average dexmedetomidine dosage in µg/kg/hour, and 24-hour average propofol dosage in µg/kg/minute on days T-1 and T+2 for each patient. RESULTS: Of 50 patients, 46 required opioids before and after tracheotomy (mean decrease of 49.4 mg OMEs). Eight patients required benzodiazepine infusion (mean decrease of 45.1 mg lorazepam equivalents. Fifteen patients required dexmedetomidine infusion (mean decrease 0.34 µg/kg/hour). Seventeen patients required propofol (mean decrease 20.5 µg/kg/minute). CONCLUSIONS: When appropriate personal protective equipment is available, use of tracheotomy in patients with COVID-19 who require MV may help to conserve medication supplies in times of extreme shortages.


Assuntos
Analgesia , COVID-19 , Dexmedetomidina , Propofol , Humanos , Hipnóticos e Sedativos/uso terapêutico , Traqueotomia , Estudos Transversais , Dexmedetomidina/uso terapêutico , Lorazepam , Estudos Retrospectivos , Dor/tratamento farmacológico , Ventiladores Mecânicos , Analgésicos/uso terapêutico , Morfina
9.
Acta Chir Orthop Traumatol Cech ; 89(5): 339-343, 2022.
Artigo em Tcheco | MEDLINE | ID: mdl-36322033

RESUMO

PURPOSE OF THE STUDY Many physicians believe that loco-regional anaesthesia and analgesia improve the postoperative course of patients indicated for total hip arthroplasty compared to general anaesthesia. However, there are many patients who refuse subarachnoid or epidural anaesthesia, or have contraindications or conditions making the use of such techniques impossible. An alternative option is the combination of general anaesthesia and a peripheral nerve blockade. The aim of this prospective randomized open-label clinical trial was to compare the efficacy and quality of postoperative analgesia between fascia iliaca block combined with general anaesthesia (GA) and subarachnoid anaesthesia with morphine and bupivacaine (SAB). MATERIAL AND METHODS After having obtained the ethics committee approval and the patients consent, a prospective, open-label, randomized trial was conducted in patients referred for total hip arthroplasty (THR). The GA group was administered ultrasound-guided fascia iliaca block with 40 ml of 0.25% bupivacaine solution after the induction of general anaesthesia. In the SAB group, subarachnoid blockade was performed with a mixture of 3 ml of 0.5% bupivacaine with 0.150 mg morphine prepared in the hospital pharmacy. Right after surgery the patients were taken to the ICU for 24 hours, after which they were transferred to a general ward. In addition to vital signs monitoring, pain intensity using a 0-10 numeric rating scale (NRS), first morphine administration at NRS >4, total morphine consumption and potential adverse effects were observed over the period of 72 hours. RESULTS There was no statistical difference between the GA (14 persons) and the SAB (14 persons) group in demographic parameters, time to first morphine administration (10 hrs vs. 19 hrs, p=0.10), number of persons with no need for morphine after surgery (5 vs. 7), tingling sensation (1 vs. 0) or numbness of the limb (0 vs. 1). There was no difference in cardiorespiratory parameters or side effects of therapy. In neither case was there respiratory depression or delayed rehabilitation. No patient developed delirium after surgery, and no patient reported dissatisfaction with pain management. DISCUSSION The fascia iliaca block and subarachnoid anaesthesia using local anaesthetic with opioid addition have been repeatedly published for patients after total hip arthroplasty, but this study is unique by comparing the two methods. The study added a new piece of knowledge to the findings of several recent meta-analyses on the comparable outcomes of general and subarachnoid anaesthesia for hip replacement in the perioperative period. CONCLUSIONS If subarachnoid anaesthesia cannot be used in hip arthroplasty, general anaesthesia with fascia iliaca block provides comparable analgesia and quality of postoperative course. Key words: total hip arthroplasty, general anaesthesia, fascia iliaca block, subarachnoid anaesthesia, postoperative analgesia, postoperative course.


Assuntos
Artroplastia de Quadril , Bloqueio Nervoso , Humanos , Morfina/uso terapêutico , Artroplastia de Quadril/efeitos adversos , Bloqueio Nervoso/métodos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Bupivacaína/uso terapêutico , Fáscia , Anestesia Geral
10.
Medicine (Baltimore) ; 101(43): e31296, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36316913

RESUMO

BACKGROUND: Nefopam is a non-opioid, non-nonsteroidal anti-imflammatory drug, analgesic drug that inhibits the reuptake of serotonin, norepinephrine, and dopamine. It is widely used as an adjuvant for pain. This study investigated whether the intraoperative, intravenous infusion of nefopam (20 mg) reduces postoperative morphine consumption, pain scores, and alleviates neuropathic pain in patients undergoing cervical spine surgery. METHODS: A prospective, paralleled design, randomized study was conducted on 50 patients (aged 18-75 years) in a university-based hospital. The patients were assigned to an intervention or a control group (25 patients in each). The intervention group received a 1-hour infusion of nefopam (20 mg) before the end of surgery. The control group received normal saline (NSS). The outcome measures were morphine consumption during the first 24 postoperative hours, numerical rating scale (NRS) pain scores, and scores for the Thai version of the Neuropathic Pain Symptom Inventory (NPSI-T) in patients with neuropathic pain and adverse drug reactions. The NPSI-T scores were assessed on the preoperative day, postoperative day 1, 3, 15, and 30. The outcome assessors were blinded to group allocation. RESULTS: Fifty patients were analyzed. During the first 24 postoperative hours, morphine consumption was 8 mg (nefopam) and 12 mg (NSS; P = .130). The intervention and control groups demonstrated no significant differences in the median NRS scores or total NPSI-T scores or adverse drug reactions. CONCLUSIONS: A single, intraoperative infusion of 20 mg of nefopam did not significantly reduce postoperative (24 hours) morphine consumption in patients undergoing anterior cervical spine surgery.


Assuntos
Analgesia , Analgésicos não Narcóticos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Nefopam , Neuralgia , Humanos , Nefopam/uso terapêutico , Analgésicos não Narcóticos/uso terapêutico , Estudos Prospectivos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/induzido quimicamente , Morfina/uso terapêutico , Neuralgia/tratamento farmacológico , Vértebras Cervicais/cirurgia , Analgésicos Opioides/uso terapêutico , Método Duplo-Cego
11.
Sci Rep ; 12(1): 19247, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357539

RESUMO

Sulpiride, as a D2-like dopamine (DA) receptor (D2R) antagonist, is an important antipsychotic drug in the treatment of schizophrenia. Recently, we have shown that the activation of D2Rs in the ventral pallidum (VP) modulates the activity of the ventral tegmental area (VTA) DAergic neurons. According to our hypothesis, intra-VP sulpiride can influence the motivational and learning processes, pervasively modifying the behavior of examined animals. In the present study, sulpiride was microinjected into the VP of male Wistar rats in three different doses. Morris water maze (MWM) test was applied to investigate the effects of sulpiride on spatial learning, while conditioned place preference (CPP) test was used to examine the potential rewarding effect of the drug. In order to show, whether the animals can associate the rewarding effect with an area which can be recognized only on its spatial location, we introduced a modified version of the CPP paradigm, the spatial CPP test. Our results show that the intra-VP sulpiride dose-dependently impairs learning processes. However, the largest dose of sulpiride induces place preference. Results of the spatial CPP paradigm demonstrate that the animals cannot associate the rewarding effect of the drug with the conditioning area based on its spatial location. In the CPP paradigm, locomotor activity decrease could be observed in the sulpiride-treated rats, likely because of a faster habituation with the conditioning environment. In summary, we can conclude that intra-VP sulpiride has a dual effect: it diminishes the hippocampus-dependent spatial learning processes, in addition, it has a dose-dependent rewarding effect.


Assuntos
Antipsicóticos , Prosencéfalo Basal , Masculino , Ratos , Animais , Sulpirida/farmacologia , Antipsicóticos/farmacologia , Prosencéfalo Basal/metabolismo , Morfina/farmacologia , Receptores de Dopamina D2/metabolismo , Ratos Wistar , Área Tegmentar Ventral/metabolismo
12.
Transl Psychiatry ; 12(1): 462, 2022 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333316

RESUMO

The present study investigates the possible therapeutic effects of human mesenchymal stem cell-derived secretome on morphine dependence and relapse. This was studied in a new model of chronic voluntary morphine intake in Wistar rats which shows classic signs of morphine intoxication and a severe naloxone-induced withdrawal syndrome. A single intranasal-systemic administration of MSCs secretome fully inhibited (>95%; p < 0.001) voluntary morphine intake and reduced the post-deprivation relapse intake by 50% (p < 0.02). Since several studies suggest a significant genetic contribution to the chronic use of many addictive drugs, the effect of MSCs secretome on morphine self-administration was further studied in rats bred as high alcohol consumers (UChB rats). Sub-chronic intraperitoneal administration of morphine before access to increasing concentrations of morphine solutions and water were available to the animals, led UChB rats to prefer ingesting morphine solutions over water, attaining levels of oral morphine intake in the range of those in the Wistar model. Intranasally administered MSCs secretome to UChB rats dose-dependently inhibited morphine self-administration by 72% (p < 0.001); while a single intranasal dose of MSC-secretome administered during a morphine deprivation period imposed on chronic morphine consumer UChB rats inhibited re-access morphine relapse intake by 80 to 85% (p < 0.0001). Both in the Wistar and the UChB rat models, MSCs-secretome administration reversed the morphine-induced increases in brain oxidative stress and neuroinflammation, considered as key engines perpetuating drug relapse. Overall, present preclinical studies suggest that products secreted by human mesenchymal stem cells may be of value in the treatment of opioid addiction.


Assuntos
Células-Tronco Mesenquimais , Transtornos Relacionados ao Uso de Opioides , Síndrome de Abstinência a Substâncias , Humanos , Animais , Ratos , Morfina/farmacologia , Ratos Wistar , Secretoma , Etanol , Recidiva , Doença Crônica , Modelos Animais , Água
13.
Nat Commun ; 13(1): 6768, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36351903

RESUMO

Opium poppy accumulates copious amounts of several benzylisoquinoline alkaloids including morphine, noscapine, and papaverine, in the specialized cytoplasm of laticifers, which compose an internal secretory system associated with phloem throughout the plant. The contiguous latex includes an abundance of related proteins belonging to the pathogenesis-related (PR)10 family known collectively as major latex proteins (MLPs) and representing at least 35% of the total cellular protein content. Two latex MLP/PR10 proteins, thebaine synthase and neopione isomerase, have recently been shown to catalyze late steps in morphine biosynthesis previously assigned as spontaneous reactions. Using a combination of sucrose density-gradient fractionation-coupled proteomics, differential scanning fluorimetry, isothermal titration calorimetry, and X-ray crystallography, we show that the major latex proteins are a family of alkaloid-binding proteins that display altered conformation in the presence of certain ligands. Addition of MLP/PR10 proteins to yeast strains engineered with morphine biosynthetic genes from the plant significantly enhanced the conversion of salutaridine to morphinan alkaloids.


Assuntos
Alcaloides , Benzilisoquinolinas , Papaver , Papaver/genética , Papaver/metabolismo , Látex/química , Alcaloides/química , Benzilisoquinolinas/metabolismo , Morfina , Saccharomyces cerevisiae/metabolismo
14.
Cell ; 185(23): 4361-4375.e19, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36368306

RESUMO

Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of µ-opioid receptor (µOR). Here, we report structures of the human µOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of µOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of µOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of µOR, which may facilitate rational design of next-generation analgesics.


Assuntos
Fentanila , Morfina , Humanos , Analgésicos Opioides/farmacologia , Arrestina/metabolismo , Fentanila/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Morfina/farmacologia , Receptores Opioides mu
15.
Pain Physician ; 25(8): 543-553, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36375182

RESUMO

BACKGROUND: Single-injection regional analgesia techniques can provide effective analgesia for abdominal hysterectomy. However, few randomized controlled trials (RCTs) have directly compared these techniques for total abdominal hysterectomy (TAH), and the best strategy remains unknown. OBJECTIVES: In this network meta-analysis, we compared the analgesic efficacy of single-injection regional analgesia techniques in patients who underwent TAH. STUDY DESIGN: A systematic review and network meta-analysis. METHODS: We searched the PubMed, Embase, Cochrane, and CINAHL databases for relevant trials from inception until April 2022. RCTs that examined single-injection regional analgesia techniques for TAH were included. Random-effects network meta-analyses were performed using the frequentist approach. The primary outcome was 24-hour cumulative morphine equivalent consumption. The secondary outcomes were pain scores, time to first request for rescue analgesia, and rates of postoperative nausea and vomiting (PONV). RESULTS: In total, 36 RCTs were included. Network meta-analyses indicated that the erector spinae plane block provided superior analgesia in terms of reduced morphine consumption, low PONV incidence, and longer time to first analgesia request. Moreover, compared with control (i.e., sham or placebo), the quadratus lumborum block provided superior analgesia in terms of time to first analgesia request and resting pain scores. LIMITATIONS: (1) Few studies have examined single-injection regional analgesia techniques other than the transversus abdominis plane block (TAPB) and wound infiltration, leading to a few indirect effect estimates. (2) Heterogeneity existed due to analgesic type/dose, plane block timing, and injection site. (3) Objective outcomes, such as length of hospital stay, were lacking; most studies only included the patient-reported subjective pain score. CONCLUSION: Single-injection blocks are effective analgesic techniques for TAH. Among them, the erector spinae plane block and quadratus lumborum block seem to have superior effects. Further studies should evaluate techniques other than TAPB and wound infiltration to draw definitive conclusions.


Assuntos
Analgesia , Dor Pós-Operatória , Humanos , Feminino , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Metanálise em Rede , Náusea e Vômito Pós-Operatórios , Analgésicos Opioides/uso terapêutico , Morfina/uso terapêutico , Analgesia/métodos , Histerectomia/efeitos adversos , Músculos Abdominais
16.
Pain Physician ; 25(8): 555-567, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36375185

RESUMO

BACKGROUND: An impaired immune system in the perioperative period has important clinical implications in patients with cancer. Despite the immunosuppressive properties of opioid therapy, it is still commonly utilized in the intrathecal or epidural space for the treatment of postoperative pain. Also, intrathecal dexmedetomidine has extended analgesic efficacy in postoperative pain; it can significantly affect immune function in perioperative patients. OBJECTIVE: To investigate the effect of intrathecal morphine, dexmedetomidine, or both in combination with bupivacaine on cellular immunity and cytokine production in cancer surgical patients. STUDY DESIGN: A prospective randomized clinical study. SETTING: South Egypt Cancer Institute, Assiut University. METHODS: Ninety patients were randomly assigned to receive intrathecal morphine 0.5 mg (Group M, n = 30), dexmedetomidine 0.5 µg/kg (Group D, n = 30) or morphine 0.5 mg with dexmedetomidine 0.5 µg/kg (Group MD n = 30); 2 mL bupivacaine 0.5% was added to injected drugs in all groups.  Blood samples were collected preoperative (T0), immediate postoperative (T1), 4 hours postoperative (T2), and 24 hours postoperative (T3) for measurement of CD3, CD4, CD4/CD8 and CD16+56(NK), interleukin(IL)-1beta (IL-1beta), IL-6, IL-10 and tumor necrosis factor alpha (TNF-alpha). RESULTS: A significant reduction in cellular immunity (CD3, CD4, CD8, CD4/CD8, CD 16+56) was noticed in the 24-hour postoperative period in all 3 studied groups, with a marked reduction in Group M in comparison to Group MD and Group D. Regarding inflammatory mediators, IL-10 and IL-1beta  showed significant reduction in Group M in the first 24-hour postoperative period in comparison to Group MD and Group D, while IL-6 was significantly reduced in Group MD and Group D in comparison to Group M in the same period. TNF-alpha was significantly increased postoperative at T1 and T2 in the 3 studied groups, then at T3 it decreased without a statistically significant difference with the preoperative level. LIMITATIONS: Our study has some limitations, such as the short period of follow-up and lack of postoperative clinical follow-up of patients to discover the association between immunity and patient outcomes. CONCLUSION: Intrathecal dexmedetomidine has the least immunosuppressive effect than morphine and morphine-dexmedetomidine, in combination with bupivacaine.


Assuntos
Neoplasias Abdominais , Dexmedetomidina , Humanos , Bupivacaína/uso terapêutico , Morfina/uso terapêutico , Dexmedetomidina/uso terapêutico , Interleucina-10/uso terapêutico , Estudos Prospectivos , Fator de Necrose Tumoral alfa/uso terapêutico , Interleucina-6/uso terapêutico , Método Duplo-Cego , Dor Pós-Operatória/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Neoplasias Abdominais/cirurgia , Anestésicos Locais/uso terapêutico
17.
Pain Physician ; 25(8): E1239-E1248, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36375196

RESUMO

BACKGROUND: Morphine is one of the preferred drugs for the clinical treatment of pain. Both clinical and preclinical studies have reported sexual dimorphism in morphine analgesia. Different circulating levels of estrogen could be involved in sex differences in response to morphine analgesia. In our previous research, we found that capsaicin injection into the cervix of rats caused acute visceral pain that could be relieved by morphine. The role of estrogen in morphine analgesia in rats under uterine cervix pain and its underlying mechanisms remain to be explored. OBJECTIVES: The present study aims to investigate the effect of estrogen on morphine analgesia and its underlying mechanism in rats under uterine cervix pain. STUDY DESIGN: Controlled animal study. SETTING: University laboratory. METHODS: First, we compared the analgesic effect of morphine in ovariectomized rats with uterine cervix pain with or without estrogen replacement. Then, the changes in the expression of opioid receptors and L-type voltage-gated calcium channels (L-type-VGCC, LTCC) at the spinal level were detected by real-time quantitative polymerase chain reaction. Finally, we investigated the effect of the manipulation of spinal LTCC (L-type CaV1.2 calcium channel, L-type CaV1.3 calcium channel) on the estrogen-mediated inhibition of morphine analgesia. RESULTS: Our study shows that morphine antinociception is  diminished in rats with uterine cervix pain that are treated with estrogen. Estrogen treatment increases the expression of spinal CaV1.2 and CaV1.3, while only anti-CaV1.2 treatment impaired estrogenic suppression of morphine antinociception. LIMITATIONS: More underlying mechanisms of the role of spinal CaV1.2 in modulating estrogen-mediated inhibition of morphine analgesia need to be explored in future research. CONCLUSIONS: This is the first evidence that spinal CaV1.2 is involved in estrogenic modulation of morphine antinociception in rats under uterine cervix pain. Our results will provide new ideas and references for estrogen-related differential prescription of opioids.


Assuntos
Morfina , Neoplasias do Colo do Útero , Ratos , Animais , Feminino , Masculino , Humanos , Morfina/farmacologia , Colo do Útero/metabolismo , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Dor Pélvica , Estrogênios/farmacologia , Estrogênios/metabolismo , Medula Espinal
18.
Pain Physician ; 25(8): E1263-E1267, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36375199

RESUMO

BACKGROUND: Obstructive sleep apnea (OSA) is the most common form of sleep-disordered breathing. While patients on chronic opioids are at increased risk of sleep-disordered breathing, there is a lack of data on the relationship between opioid dose and OSA risk in particular. The STOP-Bang Questionnaire (SBQ) is a common screening tool for OSA, but it has not been well studied in patients on chronic opioid therapy. OBJECTIVES: This study uses the SBQ to examine the relationship between total daily opioid dose and the risk of OSA in patients on chronic opioid therapy. STUDY DESIGN: Retrospective chart review. SETTING: Academic medical center pain clinic. METHODS: Patients on stable doses of chronic opioids who completed the SBQ were grouped into 3 OSA risk categories, including low (SBQ score 0-2), medium (SBQ score 3-4), and high risk (SBQ score 5-8). Morphine equivalent daily dose (MEDD) was calculated and compared between the 3 risk groups. In a secondary analysis, patients were instead grouped into opioid dose categories, including low MEDD (≤ 20), medium MEDD (21-50), and high MEDD (> 50). The SBQ scores were then compared between the 3 MEDD groups. RESULTS: The charts of 190 patients on chronic opioid therapy were reviewed. One hundred forty-seven patients did not have a prior diagnosis of OSA. Of these, 92 (63%) patients completed the SBQ. Fifty-five percent were women and 45% men. The average age was 59. The average MEDD was 23.32. In the primary analysis based on the SBQ score, 39% were low risk for OSA, 42% medium risk, and 18% were high risk. There was no difference in total MEDD between the 3 groups (P = 0.83). In the secondary analysis based on total MEDD, 58% had low MEDD, 32% had medium MEDD, and 11% had high MEDD. There was no significant difference in SBQ scores between these groups (P = 0.51). LIMITATIONS: This is a single center study, and only 63% of eligible patients completed the SBQ. The study did not attempt to control for potential confounders. The SBQ results were not confirmed with a polysomnogram. CONCLUSION: We found no relationship between the opioid dose and the risk of OSA as measured by the SBQ score in this chronic opioid population. Opioids may be more associated with sleep apnea due to central rather than obstructive processes, and additional screening tools beyond the SBQ may be needed to better screen for sleep apnea in this population.


Assuntos
Analgésicos Opioides , Apneia Obstrutiva do Sono , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Analgésicos Opioides/uso terapêutico , Estudos Retrospectivos , Apneia Obstrutiva do Sono/diagnóstico , Polissonografia , Inquéritos e Questionários , Morfina
20.
Bull Exp Biol Med ; 173(6): 730-733, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36322304

RESUMO

Activity of a peptide tuftsin analogue Selank was studied in outbred rats using the naloxone-precipitated morphine withdrawal model. Single intraperitoneal injection of Selank in an anxiolytic dose of 0.3 mg/kg reduced the total index of morphine withdrawal syndrome by 39.6%, significantly (р<0.0001) attenuated convulsive reactions, ptosis, and posture disorders, and 9-fold increased the tactile sensitivity threshold in morphine-dependent rats in comparison with the group of active control; at the same time, Selank was slightly inferior to diazepam in a dose of 2 mg/kg by pharmacological activity (the decrease in total index of morphine withdrawal syndrome by 49.3% and 13-fold increase in sensitivity threshold). Thus, Selank, like diazepam, weakens the aversive signs of morphine withdrawal in rats with opiate dependence.


Assuntos
Dependência de Morfina , Síndrome de Abstinência a Substâncias , Tuftsina , Ratos , Animais , Morfina , Dependência de Morfina/tratamento farmacológico , Naloxona/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Diazepam
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...