RESUMO
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.
Assuntos
Humanos , Morfina/farmacologia , Hiperalgesia/metabolismo , Analgésicos Opioides/farmacologia , Neurônios/metabolismo , Transdução de SinaisRESUMO
Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor (D3R) have effects on addiction in different animal models. We have previously reported that YQA14, a D3R antagonist, exhibits very high affinity and selectivity for D3Rs over D2Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D3R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
Assuntos
Ratos , Camundongos , Animais , Analgésicos Opioides , Dopamina , Heroína/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/metabolismo , Morfina/farmacologia , Comportamento Aditivo/tratamento farmacológico , AutoadministraçãoRESUMO
Abstract Objective This study aimed to investigate the impact of post-thoracotomy analgesia with dexmedetomidine and morphine on immunocytes. Methods A total of 118 patients with post-thoracotomy Patient-Controlled Intravenous Analgesia (PCIA) in our hospital from March 2016 to July 2018 were randomly selected and divided into the Composite (COM) Group (57 patients administered with dexmedetomidine [1.0 µg.kg-1 body weight] and morphine [0.48 mg.kg-1 body weight]) and the Morphine (MOR) group (61 patients administered with morphine [0.48 mg.kg-1]). The values of lymphocyte subsets (CD3+, CD4+, and CD8+) and Natural Killer cells in the peripheral blood of these two groups were detected by FACSCalibur flow cytometry at different time points (before anesthesia induction [T0], immediately after tracheal extubation [T1], 12 hours after surgery [T2], 24 hours after surgery [T3], 48 hours after surgery [T4], 72 hours after surgery [T5], and 7 days after surgery [T6]). The doses of morphine at T3 to T5 and the adverse reactions between the two groups were also recorded and compared. Results The CD3+ level and the CD4+/CD8+ ratio at T2 to T5 and the CD4+ level and NK cells at T3 to T5 were significantly higher in the COM Group than in the MOR Group (p< 0.05). The postoperative morphine dose and the incidence of postoperative itching, nausea, and vomiting were significantly lower in the COM Group than in the MOR Group (p< 0.05). Conclusions Dexmedetomidine combined with morphine for post-thoracotomy PCIA can improve the function of immunocytes, reduce morphine consumption, and reduce the adverse reactions during analgesia induction.
Resumo Objetivo Estudar o impacto em linfócitos causado pelo uso da dexmedetomidina associada à morfina para analgesia pós-toracotomia. Método Um total de 118 pacientes utilizando Analgesia Intravenosa Controlada pelo Paciente (AICP) pós-toracotomia em nosso hospital, de março de 2016 a julho de 2018, foram selecionados aleatoriamente e divididos em dois grupos: o Grupo Combinado [COM, 57 pacientes que receberam dexmedetomidina (1,0 µg.kg-1 de peso corpóreo) associada à morfina (0,48 mg.kg-1 de peso corpóreo)] e o Grupo Morfina [MOR, 61 pacientes, que receberam somente morfina (0,48 mg.kg-)]. Os valores dos subconjuntos de linfócitos (CD3+, CD4+ e CD8+) e das células NK no sangue periférico desses dois grupos foram medidos por citometria de fluxo FACSCalibur em diferentes momentos do estudo [antes da indução anestésica (T0), imediatamente após extubação traqueal (T1), 12 horas após a cirurgia (T2), 24 horas após a cirurgia (T3), 48 horas após a cirurgia (T4), 72 horas após a cirurgia (T5) e 7 dias após a cirurgia (T6)]. As doses de morfina do momento T3 ao T5 e as reações adversas entre os dois grupos também foram registradas e comparadas. Resultados O nível de CD3+ e a razão CD4+/CD8+ de T2 a T5, e o nível de CD4+ e as células NK de T3 a T5 do Grupo COM foram significantemente maiores (p< 0,05) quando comparados ao Grupo MOR. A dose de morfina no pós-operatório e a incidência de prurido, náusea e vômito no pós-operatório foram significantemente menores no grupo MOR (p< 0,05). Conclusões Dexmedetomidina combinada com morfina para AICP no período pós-toracotomia pode melhorar a função dos linfócitos, reduzir o consumo de morfina e diminuir reações adversas durante a analgesia.
Assuntos
Humanos , Masculino , Feminino , Adulto , Dor Pós-Operatória/tratamento farmacológico , Toracotomia , Células Matadoras Naturais/efeitos dos fármacos , Analgesia Controlada pelo Paciente , Subpopulações de Linfócitos/efeitos dos fármacos , Analgésicos não Narcóticos/farmacologia , Dexmedetomidina/farmacologia , Analgésicos Opioides/farmacologia , Morfina/farmacologia , Analgésicos não Narcóticos/uso terapêutico , Dexmedetomidina/uso terapêutico , Analgésicos Opioides/uso terapêutico , Pessoa de Meia-Idade , Morfina/uso terapêuticoRESUMO
Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.
Assuntos
Humanos , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Tolerância a Medicamentos , Hipoglicemiantes/farmacologia , Microglia/fisiologia , MicroRNAs/fisiologia , Minociclina/farmacologia , Morfina/farmacologia , Neuralgia/etiologia , Extratos Vegetais/farmacologia , Transdução de Sinais/fisiologiaRESUMO
SUMMARY INTRODUCTION: Opioids interact with both innate and adaptive immune systems and have direct effects on opioid receptors located on immune cells. Research on this topic has provided evidence of the opioid influence on the immune response associated with surgical stress. The immunological effects of opioids are currently being investigated, particularly whether they influence the outcome of surgery or the underlying disease regarding important aspects like infection or cancer progression. This review addresses background research related to the influence of the opioid receptor on the immune system, the immunosuppressive effect associated with major opioids during the perioperative period, and their clinical relevance. The objective of the study was to review the effects of opioids on the immune system. Methods: A search strategy was conducted in PubMed, Embase, and the Cochrane databases using the terms "immunosuppression," "immune system," "surgical procedures," "analgesics," "opioids" and "perioperative care." Results: The immunosuppressive effect of opioids was identified over 30 years ago. They include signaling and acting directly through immune cells, including B and T lymphocytes, NK cells, monocytes, and macrophages, as well as activating the downstream pathways of the hypothalamic-pituitary-adrenal (HPA) axis leading to the production of immunosuppressive glucocorticoids in the peripheral and sympathetic nervous system.
RESUMO INTRODUÇÃO: Os opioides interagem com ambos os sistemas imunes, inato e adaptativo, através de efeitos diretos sobre os receptores dos opioides localizados nas células imunes. As pesquisas neste assunto têm fornecido evidência da influência dos opioides sobre a resposta imune associada ao estresse cirúrgico. Os efeitos imunológicos dos opioides estão sendo pesquisados na atualidade, principalmente se eles determinam o resultado da cirurgia ou doença consequente devido a fatos importantes como infecção ou progressão do câncer. Essa revisão tem como alvo ver antecedentes em pesquisa relativa à influência dos receptores dos opioides no sistema imunológico, o efeito imunossupressor associado com opioides maiores durante o período peri-operatório e sua importância clínica. O objectivo da pesquisa foi revisar os efeitos dos opioides no sistema imunológico. MÉTODOS: Uma estrategia de procura foi dirigida na mídia PubMed, e no cadastro de Embase e The Cochrane, usando os termos "imunosuppressão", "sistema imunológico", "procedimentos cirúrgicos", "analgésicos", "opioides" e "cuidado peri-operatório". RESULTADOS: O efeito imunosuppressor dos opioides foi identificado há mais de 30 anos. Os efeitos imunosupressores incluem sinalização e ação diretamente através das células imunes, mesmo com os linfócitos B e T, células NK, monócitos e macrófagos, também como ativando as vias de corrente do eixo hipotálamo- hipófise- adrenal (HPA) levando à produção de glucocorticoides imunossupresores no sistema nervoso periférico e simpático.
Assuntos
Humanos , Analgésicos Opioides/farmacologia , Sistema Imunitário/efeitos dos fármacos , Tramadol/administração & dosagem , Tramadol/farmacologia , Fentanila/administração & dosagem , Fentanila/farmacologia , Imunidade Adaptativa/efeitos dos fármacos , Período Perioperatório , Remifentanil/administração & dosagem , Remifentanil/farmacologia , Analgésicos Opioides/administração & dosagem , Morfina/administração & dosagem , Morfina/farmacologiaRESUMO
ABSTRACT Purpose: To evaluate the effects of 1% morphine instillation on clinical parameters, aqueous humor turbidity, and expression levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1beta), prostaglandin E2 (PGE2), and myeloperoxidase (MPO) in rabbits with endotoxin-induced experimental uveitis. Methods: Twenty four New Zealand white rabbits were divided into four groups (n=6 each): control (CG), morphine (MG), naloxone (NG), and morphine-naloxone (MNG) groups. Under dissociative anesthesia, 0.1 mL of solution containing 0.2 µg of lipopolysaccharide (LPS) endotoxin from the Salmonella typhimurium cell wall was injected in the vitreous chamber. Clinical evaluations (conjunctical hyperemia, chemosis blepharospasm, and ocular discharge) and laser flaremetry were performed before (baseline), and 10 and 20 hours after induction of uveitis. Rabbits were subsequently euthanized and eyes were enucleated to quantify expression levels of TNF-α, IL-1 beta, PGE2, and MPO. Results: No significant differences in clinical parameters and flare values were observed between the study groups. TNF-α and IL-1 beta levels increased significantly in the CG, MG, NG, and MNG groups compared to baseline (P<0.05). Significant differences in PGE2 levels were observed between the MG and NMG groups (P<0.05). A trend toward increased MPO activity was observed in response to uveitis induction; however, this trend did not reach statistical significance (P>0.05). Conclusions: Morphine has no effect on clinical parameters, flare, or expression levels of inflammatory mediators in a rabbit model of uveitis induced by intravitreal injection of LPS.
RESUMO Objetivo: Estudaram-se os efeitos da instilação de morfina 1% sobre parâmetros clínicos, turbidez do humor aquoso e expressão de fator de necrose tumoral alfa (TNF-alfa), de interleucina-1 beta (IL-1beta), de prostaglandina E2 (PGE2) e de mieloperoxidase (MPO), em olhos de coelhos com uveíte induzida por endotoxina. Material e Métodos: Vinte e quatro coelhos da raça Nova Zelândia Branco foram distribuídos em quatro grupos (n=6, em cada): grupo controle (GC), morfina (GM), naloxona (GN) e morfina-naloxona (GMN). Sob anestesia dissociativa, injetou-se 0,1 mL de solução contendo 0,2 µg de lipossacarídeo (LPS) endotóxico da parede celular de Salmonella typhimurium na câmara vítrea. Realizou-se avaliação clínica (hiperemia conjuntival, quemose, blefaroespasmo e secreção ocular) e a flaremetria a “laser” antes (basal) e após 10 e 20 horas da indução da uveíte. No final, os coelhos foram submetidos à eutanásia e os olhos com uveíte foram enucleados para a quantificação dos níveis de TNF-alfa, IL-1 beta, PGE2 e MPO. Diferenças foram consideradas significativas quando p<0,05. Resultados: Os grupos da pesquisa não diferiram quanto aos parâmetros clínicos e os valores de “flare”. Observou-se elevação significativa nos níveis de TNF-alfa e de IL-1 beta, comparativamente ao basal, nos grupos GC, GM, GN e GMN (p<0,05). Valores de PGE2 variaram entre os grupos GM e GNM (p<0,05). A atividade de MPO aumentou após a indução da uveíte, porém, sem significância estatística (p>0,05). Conclusões: A morfina não atuou sobre parâmetros clínicos, “flare” e expressão dos mediadores inflamatórios estudados, quando instilada em olhos de coelhos com uveíte induzida por injeção intravítrea de LPS.
Assuntos
Animais , Coelhos , Analgésicos Opioides/farmacologia , Dinoprostona/análise , Interleucina-1beta/análise , Morfina/farmacologia , Peroxidase/análise , Fator de Necrose Tumoral alfa/análise , Uveíte/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Humor Aquoso/efeitos dos fármacos , Modelos Animais de Doenças , Endotoxinas , Instilação de Medicamentos , Morfina/uso terapêutico , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Tempo , Úvea/efeitos dos fármacos , Úvea/patologia , Uveíte/etiologia , Uveíte/patologiaRESUMO
Background and objectives: Esmolol is known to have no analgesic activity and no anaesthetic properties; however, it could potentiate the reduction in anaesthetic requirements and reduce postoperative analgesic use. The objective of this study is to evaluate the effect of intravenous esmolol infusion on intraoperative and postoperative analgesic consumptions as well as its effect on depth of anaesthesia. Methods: This randomized-controlled double blind study was conducted in a tertiary care hospital between March and June 2010. Sixty patients undergoing septorhinoplasty were randomized into two groups. History of allergy to drugs used in the study, ischaemic heart disease, heart block, bronchial asthma, hepatic or renal dysfunction, obesity and a history of chronic use of analgesic or β-blockers were considered cause for exclusion from the study. Thirty patients received esmolol and remifentanil (esmolol group) and 30 patients received normal saline and remifentanil (control group) as an intravenous infusion during the procedure. Mean arterial pressure, heart rate, and bispectral index values were recorded every 10min. Total remifentanil consumption, visual analogue scale scores, time to first analgesia and total postoperative morphine consumption were recorded. Results: The total remifentanil consumption, visual analogue scale scores at 0, 20 and 60 min, total morphine consumption, time to first analgesia and the number of patients who needed an intravenous morphine were lower in the esmolol group. Conclusions: Intravenous infusion of esmolol reduced the intraoperative and postoperative analgesic consumption, reduced visual analogue scale scores in the early postoperative period and prolonged the time to first analgesia; however it did not influence the depth of anaesthesia. .
Justificativa e objetivos: Esmolol é conhecido por não ter atividade analgésica e propriedades anestésicas; porém, pode potenciar a redução da necessidade de anestésicos e reduzir o uso de analgésicos no pós-operatório. O objetivo deste estudo foi avaliar o efeito da infusão de esmolol por via intravenosa sobre o consumo de analgésico durante os períodos intraoperatório e pós-operatório, bem como seu efeito sobre a profundidade da anestesia. Métodos: Este estudo randômico, controlado e duplo-cego foi conduzido em um hospital terciário entre março e junho de 2010. Foram randomicamente divididos em dois grupos 60 pacientes programados para serem submetidos à septorrinoplastia. História de alergia aos medicamentos usados no estudo, isquemia cardíaca, bloqueio cardíaco, asma brônquica, insuficiência hepática ou renal, obesidade e história de uso crônico de analgésicos ou β-bloqueadores foram os critérios de exclusão. Trinta pacientes receberam esmolol e remifentanil (grupo esmolol) e 30 receberam soro fisiológico e remifentanil (grupo controle) via perfusão intravenosa. Pressão arterial média, frequência cardíaca e valores do índice bispectral foram registrados a cada 10 minutos. Consumo total de remifentanil, escores da escala visual analógica, tempo para a primeira analgesia e consumo total de morfina no pós-operatório foram registrados. Resultados: O consumo total de remifentanil, os escores da escala visual analógica nos minutos 0, 20 e 60, o consumo total de morfina, o tempo para a primeira analgesia e o número de pacientes que precisaram de morfina intravenosa foram menores no grupo esmolol. Conclusões: Esmolol em infusão intravenosa reduziu o consumo de analgésicos tanto no intraoperatório ...
Justificación y objetivos: El esmolol se conoce porque no posee actividad añalgésica ni propie-dades anestésicas; sin embargo, puede potenciar la reducción de la necesidad de anestésicos y disminuir el uso de analgésicos en el postoperatorio. El objetivo de este estudio fue evaluar el efecto de la infusión de esmolol por vía intravenosa sobre el consumo de analgésico durante los períodos intraoperatorio y postoperatorio, como también su efecto sobre la profundidad de la anestesia. Métodos: Este estudio aleatorizado, controlado y doble ciego fue llevado a cabo en un hospital terciario entre marzo y junio de 2010. Sesenta pacientes programados para someterse a la septorrinoplastia fueron aleatoriamente divididos en 2 grupos. El historial de alergia a los medicamentos usados en el estudio, isquemia cardíaca, bloqueo cardíaco, asma bronquial, insuficiencia hepática o renal, obesidad e historial de uso crónico de analgésicos o ß-bloqueantes, fueron los criterios de exclusión del estudio. Treinta pacientes recibieron esmolol y remifenta-nilo (grupo esmolol) y 30 pacientes recibieron suero fisiológico y remifentanilo (grupo control), vía perfusión intravenosa durante el procedimiento. La presión arterial media, frecuencia cardíaca y valores del índice biespectral fueron registrados cada 10 min. Se registraron el consumo total de remifentanilo, puntuaciones de la escala visual analógica, tiempo para la primera analgesia y el consumo total de morfina en el postoperatorio. Resultados: El consumo total de remifentanilo, las puntuaciones de la escala visual analógica en los minutos 0, 20 y 60, el consumo total de morfina, el tiempo para la primera analgesia y el número de pacientes que necesitaron morfina intravenosa fueron menores en el grupo esmolol. Conclusiones: El esmolol en infusión intravenosa ...
Assuntos
Humanos , Adulto , Pessoa de Meia-Idade , Antagonistas Adrenérgicos beta/farmacologia , Morfina/farmacologia , Septo Nasal/cirurgia , Método Duplo-Cego , Monitores de Consciência , Anestésicos/farmacologiaRESUMO
Morphine is a potent analgesic opioid used extensively for pain treatment. During the last decade, global consumption grew more than 4-fold. However, molecular mechanisms elicited by morphine are not totally understood. Thus, a growing literature indicates that there are additional actions to the analgesic effect. Previous studies about morphine and oxidative stress are controversial and used concentrations outside the range of clinical practice. Therefore, in this study, we hypothesized that a therapeutic concentration of morphine (1 μM) would show a protective effect in a traditional model of oxidative stress. We exposed the C6 glioma cell line to hydrogen peroxide (H2O2) and/or morphine for 24 h and evaluated cell viability, lipid peroxidation, and levels of sulfhydryl groups (an indicator of the redox state of the cell). Morphine did not prevent the decrease in cell viability provoked by H2O2 but partially prevented lipid peroxidation caused by 0.0025% H2O2 (a concentration allowing more than 90% cell viability). Interestingly, this opioid did not alter the increased levels of sulfhydryl groups produced by exposure to 0.0025% H2O2, opening the possibility that alternative molecular mechanisms (a direct scavenging activity or the inhibition of NAPDH oxidase) may explain the protective effect registered in the lipid peroxidation assay. Our results demonstrate, for the first time, that morphine in usual analgesic doses may contribute to minimizing oxidative stress in cells of glial origin. This study supports the importance of employing concentrations similar to those used in clinical practice for a better approximation between experimental models and the clinical setting.
Assuntos
Animais , Ratos , Analgésicos Opioides/farmacologia , Glioma/tratamento farmacológico , Peróxido de Hidrogênio/administração & dosagem , Morfina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular , Sequestradores de Radicais Livres/farmacologia , Glioma/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Modelos Biológicos , Morfina/administração & dosagem , Oxirredução , Fatores de Proteção , Compostos de Sulfidrila/análiseRESUMO
Glial cells play a critical role in morphine tolerance, resulting from repeated administration of morphine. Both the development and the expression of tolerance are suppressed by the analgesic lamotrigine. This study investigated the relationship between the ability of lamotrigine to maintain the antinociceptive effect of morphine during tolerance development and glial cell activation in the spinal cord. In a rat model, morphine (15 microg) was intrathecally injected once daily for 7 days to induce morphine tolerance. Lamotrigine (200 microg) was co-administered with morphine either for 7 days or the first or last 3 days of this 7 day period. Thermal nociception was measured. OX-42 and GFAP immunoreactivity, indicating spinal microglial and astrocytic activation were evaluated on day 8. Tolerance developed after 7 days of intrathecal morphine administration; however, this was completely blocked and reversed by co-administration of lamotrigine. When lamotrigine was coinjected with morphine on days 5-7, the morphine effect was partially restored. Glial cell activation increased with the development of morphine tolerance but was clearly inhibited in the presence of lamotrigine. These results suggest that, in association with the suppression of spinal glial cell activity, intrathecally coadministered lamotrigine attenuates antinociceptive tolerance to morphine.
Assuntos
Animais , Masculino , Ratos , Analgésicos/farmacologia , Antígeno CD11b/metabolismo , Astrócitos/citologia , Tolerância a Medicamentos , Imuno-Histoquímica , Microglia/citologia , Morfina/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/citologia , Ratos Sprague-Dawley , Medula Espinal/citologia , Triazinas/farmacologiaRESUMO
It is demonstrated that morphine and tramadol affects seizure but the mode of action of these drugs on seizure has not been compared yet with increasing of age. The aim of this study was to compare the impact of exposure to these drugs on Pentylenetetrazol-induced seizure in immature rat. Male neonate rats were randomly chosen and divided into three groups namely Saline [n=21], Morphine [n=12] and Tramadol [n=13]. On postnatal days 8-14, Saline group received normal saline and two other groups received morphine and tramadol with additive doses, respectively. On postnatal days 22-28, the saline treated rats divided into three subgroups and received saline [n=8], morphine [n=8] or tramadol [n=5]. Morphine treated rats received saline or morphine [each n=6], and tramadol treated rats received saline [n=7] or tramadol [n=6]. At postnatal day 29, they were evaluated for PTZ-induced seizure. Number of tonic-clonic seizure was increased in all groups compared with control and tramadol+saline groups [P<0.05]. Duration of tonic-clonic seizure was decreased in tramadol+saline group compared with other tramadol groups [P<0.05]. Latency of tonic-clonic seizurewas decreased in tramadol+saline group compared with control rats [P<0.05], But it was increased in saline+tramadol group compared with other groups except to saline group [P<0.05]. Latency of myoclonic contractions in saline+morphine and saline+tramadol groups was lower than in control rats [P<0.05]. Similar age-related changes may occur inchronic exposure to morphine and tramadol in the neonatal period which leads to an increase in severity of seizures in rats on postnatal days 22-28. The effect of morphine and tramadol does not show any significant difference
Assuntos
Masculino , Animais de Laboratório , Morfina/farmacologia , Tramadol/farmacologia , Morfina/administração & dosagem , Tramadol/administração & dosagem , Convulsões/induzido quimicamenteRESUMO
Post operative pain is cause of suffering in most patients and can cause a lot of problems. Analgesic effects of many narcotics have been widely studied. In this study, the effects of methadone and morphine on postoperative pain scale following thoracic surgery in opium addict patients were assessed. In this clinical trial and double blind study, sixty opium addict patients [ASA I, II], aged 20-65 yr, were randomly allocated into two groups. Thirty minutes before induction of general anesthesia the first group received 0.1 mg/kg methadone and the second group received 0.1 mg/kg morphine. The two groups were assessed and compared in regard to the intensity of pain and meperidine requirement in the first post operative 24 hr. Intensity of post operative pain and meperidine requirement in the methadone group were significantly lower than those in the morphine group [P<0.01]. Administration of 0.1mg/kg methadone as premedication for opium addict patients reduces the post operative pain more than morphine. Therefore, premedication with methadone for opium addict patients undergoing thoracic surgery is recommended
Assuntos
Humanos , Morfina/farmacologia , Dor Pós-Operatória/tratamento farmacológico , Ópio , Transtornos Relacionados ao Uso de Opioides , Cirurgia Torácica , Método Duplo-Cego , MeperidinaRESUMO
JUSTIFICATIVA E OBJETIVOS: A associação de anestésicos locais (AL) a adjuvantes por via subaracnóidea melhora a qualidade do bloqueio e prolonga a duração da analgesia. Foram avaliados os efeitos maternos e as repercussões neonatais da associação de sufentanil, morfina e clonidina à bupivacaína hiperbárica em cesariana eletiva. MÉTODO: Estudo prospectivo, randomizado, encoberto, com 96 pacientes distribuídas em quatro grupos: GI (sem adjuvante); GII (sufentanil; 5,0 µg); GIII (morfina; 100 µg); e GIV (clonidina; 75 µg). Foram avaliados: início e nível de bloqueio sensitivo; analgesia peroperatória; grau e tempo para regressão do bloqueio motor; duração da analgesia; sedação; repercussões materno-fetais. RESULTADOS: O início do bloqueio foi significativamente menor nos grupos com adjuvantes em comparação com o Grupo I. No peroperatório, pacientes dos Grupos I e III referiram dor. A duração da analgesia foi significativamente maior no Grupo II e o tempo para desbloqueio motor foi significativamente maior no Grupo IV. Prurido ocorreu nos grupos II e III. A sedação foi significativa no Grupo IV. A hipotensão arterial foi prolongada no Grupo IV. CONCLUSÃO: A adição de sufentanil e clonidina à bupivacaína hiperbárica proporcionou adequada anestesia para cesariana e boa analgesia pós-operatória. A clonidina causou mais sedação peroperatória e maior tempo para desbloqueio motor. O prurido foi evidente quando do emprego de opioides.
BACKGROUND AND OBJECTIVES: Combination of local anesthetics (LA) with adjuvants for spinal anesthesia improves block quality and prolongs the duration of analgesia. It was evaluated the maternal effects and neonatal repercussions of sufentanil, morphine, and clonidine combined with hyperbaric bupivacaine for elective cesarean section. METHOD: Prospective, randomized, blinded study of 96 patients allocated into four groups: Group I (no adjuvant), Group II (sufentanil 5.0 µg), Group III (morphine 100 µg), and Group IV (clonidine 75 µg). It was evaluated the onset and level of sensory block, perioperative analgesia, degree and recovery time of motor block, duration of analgesia, sedation, and maternal-fetal repercussions. RESULTS: The onset of blockade was significantly faster in groups with adjuvants compared with Group I. Patients in Groups I and III reported pain during the perioperative period. Duration of analgesia was significantly higher in Group II and time to motor block recovery was significantly higher in Group IV. Pruritus occurred in Groups II and III. Sedation was significant in Group IV and there was prolonged arterial hypotension in Group IV. CONCLUSION: Addition of sufentanil and clonidine to hyperbaric bupivacaine provided adequate anesthesia for cesarean section and good postoperative analgesia. Clonidine caused more perioperative sedation and longer time to motor block recovery. Pruritus was evident when opioids were used.
JUSTIFICATIVA Y OBJETIVOS: La asociación de anestésicos locales (AL) a adyuvantes por vía subaracnoidea mejora la calidad del bloqueo y prolonga la duración de la analgesia. Se evaluaron los efectos maternos y las repercusiones neonatales de la asociación de sufentanil, morfina y clonidina a la bupivacaina hiperbárica en la cesárea electiva. MÉTODO: Estudio prospectivo, randomizado, encubierto, con 96 pacientes distribuidas en cuatro grupos: GI (sin adyuvante); GII (sufentanil; 5,0 µg); GIII (morfina; 100 µg); y GIV (clonidina; 75 µg). Se evaluaron: el inicio y el nivel de bloqueo sensitivo; analgesia peroperatoria; el grado y el tiempo para la regresión del bloqueo motor; la duración de la analgesia; la sedación; y las repercusiones materno-fetales. RESULTADOS: El inicio del bloqueo fue significativamente menor en los grupos con adyuvantes en comparación con el Grupo I. En el perioperatorio, los pacientes de los Grupos I y III dijeron sentir dolor. La duración de la analgesia fue significativamente mayor en el Grupo II y el tiempo para el desbloqueo motor fue significativamente mayor en el Grupo IV. El prurito apareció en los grupos II y III. La sedación fue significativa en el Grupo IV. La hipotensión arterial se prolongó en el Grupo IV. CONCLUSIONES: La adición de sufentanil y clonidina a la bupivacaina hiperbárica proporcionó una adecuada anestesia para la cesárea como también una buena analgesia postoperatoria. La clonidina causó más sedación perioperatoria y un mayor tiempo para el desbloqueo motor. El prurito fue evidente cuando se usaron los opioides.
Assuntos
Humanos , Feminino , Gravidez , Bupivacaína/farmacologia , Cesárea/instrumentação , Raquianestesia/instrumentação , Estudos Prospectivos , Clonidina/farmacologia , Sufentanil/farmacologia , Composição de Medicamentos , Morfina/farmacologiaRESUMO
In previous studies it has been emphasized that the site of morphine action may be either in the embryo or the placenta. In the present study, we attempt to identify the site of morphine action on the fetal section of Wistar rat placenta by using C14-morphine. In this study [experimental], female Wistar rats [weights: 170-200 g] were mated with male rats and their coupling times recorded. Experimental groups received daily doses of 0.05 mg/ml of C14-morphine in their drinking water. On the 9[th] and 14[th] embryonic days, the pregnant rats were anesthetized and the placenta and uterus surgically removed. Placentas were fixed in 10% formalin for two weeks, then processed, sectioned in 5 micro m and 25 micro m thicknesses, and fixed on glass slides for further evaluation. The 25 micro m sections were delivered to black and white film for three days. Films were processed and evaluated with a digital inverse microscope for possible radiological impression. The 5 micro m sections were processed for hematoxylin and eosin [H and E] staining, and evaluated by light microscope and MOTIC software. Our results indicated that the site of action of C14-morphine was possibly located on the blood plexus of the fetal portion of the placenta. In addition, oral morphine consumption was shown to inhibit fetal and maternal placental development in the experimental groups. We conclude that morphine's effectiveness on the reduction of embryo growth and development may be via its effects on the blood plexus of the fetal section of the placenta
Assuntos
Animais de Laboratório , Morfina/farmacologia , Ratos Wistar , PrenhezRESUMO
A large reservoir of bacterial lipopolysaccharide (LPS) is available in the colon and this could promote colon cancer metastasis by enhancing tumor cell adhesion, intravasation, and extravasation. Furthermore, adhesion molecules like ICAM-1, VCAM-1, and E-selectin play important roles in the adhesion of tumor cells to endothelium. This study was designed to determine whether morphine can attenuate the expressions of adhesion molecules up-regulated by the supernatant of LPS-stimulated HCT 116 colon cancer cells (LPS-Sup). In this study, we divided to three groups by cell-growth medium of human umbilical vascular endothelial cells (HUVECs): the control group was incubated in growth factor-free endothelial medium, the Sup group was incubated in the supernatant of HCT 116 cells (Sup), and the LPS-Sup group was incubated in LPS-Sup. To observe effect of morphine to the adhesion molecules expressions in the LPS-Sup group, we co-treated morphine with LPS or added it to LPS-Sup. Adhesion molecule expressions on HUVECs in all three groups were measured during incubation period. Consquentially, ICAM-1, VCAM-1, and E-selectin expressions on HUVECs were significantly lower when morphine was co-treated with LPS than not co-treated. Thus, we suggest that morphine affects the expressions of adhesion molecules primarily by attenuating LPS stimuli on tumor cells.
Assuntos
Humanos , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Selectina E/metabolismo , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos/toxicidade , Morfina/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
The purpose of this study is to determine 1) whether morphine postconditiong (MPostC) can attenuate the intercellular adhesion molecules-1 (ICAM-1) expression after reoxygenation injury and 2) the subtype(s) of the opioid receptors (ORs) that are involved with MPostC. Human umbilical vein endothelial cells (HUVECs) were subjected to 6 hr anoxia followed by 12 hr reoxygenation. Three morphine concentrations (0.3, 3, 30 microM) were used to evaluate the protective effect of MPostC. We also investigated blockading the OR subtypes' effects on MPostC by using three antagonists (a micro-OR antagonist naloxone, a kappa-OR antagonist nor-binaltorphimine, and a delta-OR antagonist naltrindole) and the inhibitor of protein kinase C (PKC) chelerythrine. As results, the ICAM-1 expression was significantly reduced in the MPostC (3, 30 microM) groups compared to the control group at 1, 6, 9, and 12 hours reoxygenation time. As a consequence, neutrophil adhesion was also decreased after MPostC. These effects were abolished by coadministering chelerythrine, nor-binaltorphimine or naltrindole, but not with naloxone. In conclusion, it is assumed that MPostC could attenuate the expression of ICAM-1 on endothelial cells during reoxygenation via the kappa and delta-OR (opioid receptor)-specific pathway, and this also involves a PKC-dependent pathway.
Assuntos
Animais , Humanos , Benzofenantridinas/farmacologia , Células Endoteliais/citologia , Endotélio Vascular/citologia , Molécula 1 de Adesão Intercelular/genética , Morfina/farmacologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Isoformas de Proteínas/metabolismo , Proteína Quinase C/antagonistas & inibidores , Receptores Opioides/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/fisiologia , Veias Umbilicais/citologiaRESUMO
Elaeagnus angustifolia extract has been used for its antinociceptive effects. The present study was done to compare of different dosage of this plant extract with and without Morphine on the extent of the antinociceptive effect. This study was done on the 80 male NMRI mice with a mean weight of 28 +/- 3G. These animals were divided to 10 groups [8 mice in each group] including: control, positive control, group treated with morphine [2 mg/kg], group treated with E. angustifolia aqueous extract [62.5, 125 and 250 mg/kg] and group treated with the plant aqueous extract plus morphine. Study was done on the 80 mice in two stages: with and without morphine and with three dosages of E.angustifolia aqueous extract. The extract was injected through the intraperitoneal route, [i.p] 30 minutes before the writhing test. Normal saline was injected in the control group and indomethacin, [5 mg/kg] to the positive control group. Then, the increase in abdominal pulse was calculated for 30 minutes as a sign of visceral pain and the pulse rates were compared in the different groups. Pulse rate in the control group was 88.4 +/- 2.4. These rates were 39.6 +/- 2.4 when 62.5 mg/kg E. angustifolia was used without morphine and 9.3 +/- 1.4 with same dosage of extract with morphine [p<0.0001]. Moreover, our findings showed that antinociceptive effect increased with higher dosages of plant extract [p<0.001]. Elaeagnus angustifolia and morphine show evidence of synergistic effect for antinociception in mice
Assuntos
Animais de Laboratório , Masculino , Morfina/farmacologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Analgésicos , Medição da Dor/efeitos dos fármacosRESUMO
Detection of morphine, fentanyl, and tramadol in human hair and in hair, bone and bone marrow of rats was done using high pressure liquid chromatography [HPKC]. Forty participants were divided into 4 groups control, morphine, tramadol, and fentanyl group. Hair samples were taken after 7 days of exposure to the tested drugs. The animal pat of the experiment consisted of 80 rats. The first 40 rats were divided into 4 subgroups [10 rats each]. The first subgroup was injected with saline IP as a control group, the second subgroup was injected with morphine 20mg/kg SC. The 3[rd] subgroup was injected with fentanyl 60micro g/kg IP and the 4[th] one was injected with tramadol 20mg/kg IP. Hair specimens were collected ten days after injection. The other forty rats were divided into 4 subgroups treated with the same drug doses of the first 40 rats, but morphine and tramadol groups were scarificed after 1 hour and fentanyl group was scarificed after 20 minutes. Femora diaphysis and bone marrow were collected from each sacrificed rat and frozen. After extraction; HPLC was used to evaluate if these drugs could be detected in these tissues after exposure to single therapeutic doses or not. Results showed that all control groups gave negative results. Morphine, fentanyl and tramadol were detected in human hair at levels 20-123pg/mg, 0.6-1.3 and 1.23-4.23 ng/mg respectively. In rats; morphine was detected at level 0.03-0.53, 4.39-12.31 and 9.31-31.20 ng/mg in hair, bone and bone marrow of rats respectively. Fentanyl was detected at level 1.9-6.20, 5.35-22.36 and 18.22-53.49 ng/mg while tramadol was detected at level 1.27-3.92, 9.6-21.6, and 22.62 to 51.31 ng/mg in hair, bone and bone marrow respectively. This study confirmed that morphine, fentanyl and tramadol are detectable even after single use in hair, bone and bone marrow
Assuntos
Humanos , Animais de Laboratório , Morfina/farmacologia , Fentanila/farmacologia , Tramadol/farmacologia , Monitoramento de Medicamentos , Osso e Ossos , Medula Óssea , Cabelo , Cromatografia Líquida de Alta Pressão/métodos , Humanos , RatosRESUMO
Postanesthesia shivering is an undesirable event that may induce a variety of adverse consequences including patient discomfort, increased oxygen consumption and wound pain. Thus, its pharmacological treatment should be regarded. The purpose of this study was to compare the efficacy of morphine, fentanyl and pethidine for the treatment of postanesthesia shivering. Fifty patients who developed shivering were treated in a randomized double blinded manner with an intravenous bolus dose of 2 or 4 mg morphine, 25 or 50 mg pethidine, and 50 microg fentanyl. Then, they were monitored for 30 minutes and the shivering suppression grade, the time taken to stop shivering, the shivering cessation time, recurrence of shivering and opioid side effects were evaluated. Core body temperature was measured immediately before, and at 15 and 30 minute after administering the drug. The groups did not differ significantly regarding shivering suppression grade, shivering cessation time, and recurrence of shivering. There was a significant difference in the time taken to stop shivering between groups. Following injection of the drugs, the core temperatures increased in the five groups with statistical difference. All opioids were effective in treating postanesthesia shivering in a similar extent
Assuntos
Humanos , Masculino , Feminino , Morfina/farmacologia , Meperidina/farmacologia , Fentanila/farmacologia , Anestesia/efeitos adversos , Temperatura Corporal/efeitos dos fármacos , Método Duplo-Cego , Complicações Pós-Operatórias/tratamento farmacológico , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate the effect of opioid receptor blockade on the myocardial protection conferred by chronic exercise and to compare exercise training with different strategies of myocardial protection (opioid infusion and brief periods of ischemia-reperfusion) preceding irreversible left anterior descending coronary ligation. INTRODUCTION: The acute cardioprotective effects of exercise training are at least partly mediated through opioid receptor-dependent mechanisms in ischemia-reperfusion models. METHODS: Male Wistar rats (n = 76) were randomly assigned to 7 groups: (1) control; (2) exercise training; (3) morphine; (4) intermittent ischemia-reperfusion (three alternating periods of left anterior descending coronary occlusion and reperfusion); (5) exercise training+morphine; (6) naloxone (a non-selective opioid receptor blocker) plus morphine; (7) naloxone before each exercise-training session. Myocardial infarction was established in all groups by left anterior descending coronary ligation. Exercise training was performed on a treadmill for 60 minutes, 5 times/week, for 12 weeks, at 60 percent peak oxygen (peak VO2). Infarct size was histologically evaluated. RESULTS: Exercise training significantly increased exercise capacity and ΔVO2 (VO2 peak - VO2 rest) (p<0.01 vs. sedentary groups). Compared with control, all treatment groups except morphine plus naloxone and exercise training plus naloxone showed a smaller infarcted area (p<0.05). No additional decrease in infarct size occurred in the exercise training plus morphine group. No difference in myocardial capillary density (p = 0.88) was observed in any group. CONCLUSIONS: Exercise training, morphine, exercise training plus morphine and ischemia-reperfusion groups had a smaller infarcted area than the control group. The effect of chronic exercise training in decreasing infarct size seems to occur, at least in part, through the opioid receptor stimulus and not by increasing ...
Assuntos
Animais , Masculino , Ratos , Infarto do Miocárdio/prevenção & controle , Condicionamento Físico Animal/fisiologia , Receptores Opioides/antagonistas & inibidores , Estudos de Casos e Controles , Cardiotônicos/farmacologia , Morfina/farmacologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Entorpecentes/farmacologia , Consumo de Oxigênio/fisiologia , Esforço Físico/fisiologia , Distribuição Aleatória , Ratos Wistar , Fatores de TempoRESUMO
OBJECTIVE: The study was performed to assess the effect of potassium channel openers on morphine tolerance and vice-versa. METHODS: Swiss albino mice of either gender weighing between 25-30 g were used for the study. The study assesses the effect of potassium channel openers (cromakalim, diazoxide and minoxidil) on morphine tolerance and vice-versa, using formalin and tail-flick tests. RESULTS: The antinociceptive effect of cromakalim and minoxidil was significantly reduced when administered to morphine-tolerant mice, in both the behavioural tests. However, reduced analgesic effect of diazoxide was observed on morphine-tolerance in the formalin test but not in the tail-flick test. Tolerance was observed when morphine was administered to animals chronically treated with any of the potassium channel openers. The same effect was observed when morphine was injected into a group treated with a combination of morphine and any of the potassium channel openers. CONCLUSIONS: This study, therefore, suggests that both morphine and potassium channel openers are cross-tolerant. However, such interaction occurs at the level of potassium channels rather than at the level of receptors.
OBJETIVO: El estudio fue realizado para evaluar el efecto de los abridores de canales de potasio en la tolerancia a la morfina, y viceversa. MÉTODOS: Para el estudio, se usaron ratones albinos suizos de ambos sexos que pesaban entre 25-30 g. El estudio evalúa el efecto de los abridores de canales de potasio (cromacalina, diazóxido y minoxidil) en la tolerancia a la morfina, y viceversa, usando la prueba de la sacudida de la cola y la prueba de la formalina. RESULTADOS: El efecto antinociceptivo de la cromacalina y el minoxidil fue significativamente reducido cuando se le administró a los ratones tolerantes a la morfina, en ambas pruebas conductuales. Sin embargo, se observó un efecto analgésico reducido de diazóxido sobre la tolerancia a la morfina en la prueba de la formalina, pero no en la prueba de la sacudida de la cola. Se observó tolerancia al administrar morfina a animales crónicamente tratados con cualquiera de los abridores de canales de potasio. El mismo efecto fue observado cuando se inyectó la morfina al grupo tratado con una combinación de morfina y cualquiera de los abridores de canales de potasio. CONCLUSIONES: Por consiguiente, este estudio sugiere que tanto la morfina como los abridores de canales de potasio son tolerantes cruzados. Sin embargo, tal interacción ocurre a nivel de los canales de potasio más bien que a nivel de los receptores.