RESUMEN
The rostral ventromedial medulla (RVM) is highly involved in pain signal transmissions. Previous studies have shown that thalidomide is anti-nociceptive. Thus, we evaluated the neurobiological mechanisms of thalidomide in the RVM in the regulation of postoperative pain. We used a rat model of postoperative pain to investigate the effects of intra-RVM thalidomide treatments on postoperative pain, and evaluate the role of cannabinoid receptors in the effects of intra-RVM thalidomide treatments on GABAergic neurotransmission in the RVM neurons. We found intra-RVM thalidomide treatments reduced incisional surgery induced mechanical allodynia. This phenomenon was associated with attenuation of the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) and spontaneous IPSCs (sIPSCs) in RVM neurons. Furthermore, applications of WIN 55,212-3 mesylate, a non-selective cannabinoid receptor antagonist reversed the effects of repeated thalidomide treatment on the frequency but not the amplitude of mIPSCs and sIPSCs. Finally, we found that repeated thalidomide treatment robustly enhanced CB2 receptor expression, but slightly reduced CB1 receptor expression, in the RVM. These results suggested that the antinociceptive effects of thalidomide in the RVM likely involve the attenuation of GABA release, which are critically regulated by cannabinoid receptors.
Asunto(s)
Analgésicos/uso terapéutico , Bulbo Raquídeo/fisiología , Dolor Postoperatorio/tratamiento farmacológico , Talidomida/uso terapéutico , Animales , Modelos Animales de Enfermedad , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Masculino , Bulbo Raquídeo/citología , Bulbo Raquídeo/efectos de los fármacos , Neuronas/efectos de los fármacos , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Quinoxalinas/farmacología , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacología , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
Opioid analgesics have less efficacy in diabetic neuropathy treatment, and tolerance often occurs after chronic usage. Given that thalidomide can potentiate the morphine efficacy in diabetic neuropathy treatment, we investigated the effects of intrathecal administrations of thalidomide on morphine tolerance during the treatment of diabetic neuropathy. We found that intrathecal administrations of thalidomide (25 mg/kg/ml) potentiated the analgesic effects of morphine on mechanical hyperalgesia and prevented the development of morphine tolerance. While this treatment regimen did not alter the protein levels of µ-opioid receptor (MOR) in the spinal cord of diabetic rats, chronic morphine treatment robustly increased MOR binding density in the synaptic plasma membranes fraction, but decreased it in the microsomal fraction. Furthermore, thalidomide was able to reverse the distribution of MOR altered by chronic morphine treatment. Finally, STZ-induced diabetes promoted PKC activation and enhanced TNFα level in the spinal cord, which were attenuated by intrathecal administrations of thalidomide. Taken together, these results suggested that thalidomide may potentiate morphine efficacy on diabetic neuropathy and prevent the development of morphine tolerance by suppressing PKC activation and TNFα level in the spinal cord.
Asunto(s)
Analgésicos Opioides/farmacología , Neuropatías Diabéticas/tratamiento farmacológico , Morfina/farmacología , Talidomida/farmacología , Analgésicos Opioides/uso terapéutico , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/fisiopatología , Sinergismo Farmacológico , Tolerancia a Medicamentos , Activación Enzimática , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Infusiones Intravenosas , Inyecciones Espinales , Masculino , Morfina/uso terapéutico , Estimulación Física , Proteína Quinasa C/metabolismo , Ratas Sprague-Dawley , Receptores Opioides mu/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Estreptozocina , Talidomida/uso terapéutico , Tacto , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The rostral ventromedial medulla (RVM) plays a critical role in pain signal transmissions. However, the mechanisms of RVM in type 2 diabetic neuropathy are still poorly understood. Therefore, we evaluated the mechanisms within the RVM in the modulation of neuropathic pain in type 2 diabetes. To this end, we used Zucker diabetic fatty (ZDF) rats to examine the levels of TNFα, IL-1ß, and NF-κB in the RVM during the development of neuropathic pain in type 2 diabetes, and evaluated the effects of intra-RVM microinjections of thalidomide on the levels of TNFα, IL-1ß, and NF-κB in the RVM and mechanical allodynia and thermal hyperalgesia induced by type 2 diabetes. We found that ZDF rats became hyperglycemic and exhibited increased levels of TNFα, IL-1ß, and NFκB in the RVM at the age of 13 weeks. Intra-RVM administrations of thalidomide dose-dependently attenuated mechanical allodynia and thermal hyperalgesia, and this phenomenon was associated with reduced levels of TNFα, IL-1ß, and NFκB in the RVM, without altering serum levels of TNFα or IL-1ß. These results suggested that supraspinal mechanisms of thalidomide play a critical role in modulations of type 2 diabetes induced neuropathic pain, which is likely mediated by TNFα and IL-1ß in the RVM.
Asunto(s)
Neuropatías Diabéticas/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Bulbo Raquídeo/efectos de los fármacos , Talidomida/uso terapéutico , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Citocinas/sangre , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/patología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Masculino , Bulbo Raquídeo/fisiología , Microinyecciones , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas ZuckerRESUMEN
Intervertebral disc (IVD) disease, the most common cause of disc failure and low back pain, is characterized by age-related changes in the adult disc. In this study we aimed to analyze the potential of thalidomide for the treatment of IVD disease, through identifying and explaining its anti-inflammatory and anti-catabolic activity in both in vitro IVD cell culture and in vivo animal model. Inflammatory response was induced by IL-1ß, then the activity and expression of inflammatory mediators and pathways were assessed in the presence or absence of thalidomide. The p38 inhibitor SB203580 was also used to investigate the involvement of the MAPK pathway in the observed effects. Moreover the analgesic properties of thalidomide were analyzed by the von Frey filament test in Sprague-Dawley rats. Our results indicated that thalidomide significantly inhibited the expression of pro-inflammatory mediators and matrix metalloproteinases in vitro, as well as radiculopathic pain in vivo, most probably by modulation of the activity of IRAK-1 and its downstream effectors p38, JNK and NF-κB. Our current study strongly supports the potential of thalidomide for the treatment of pain and inflammation in degenerative disc disease.
Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Radiculopatía/tratamiento farmacológico , Talidomida/uso terapéutico , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Células Cultivadas , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , FN-kappa B/metabolismo , Dolor/metabolismo , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Radiculopatía/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Talidomida/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The management of patients with neuropathic pain is challenging. Monotherapy with a single pain relief drug may encounter different difficulties, such as short duration of efficacy and hence too many times of drug administration, and inadequate drug delivery. Recently, nanocarrier-based drug delivery systems have been proved to provide promising strategies for efficient drug loading, delivery, and release. In the present study, we developed poly(ethylene glycol) methyl ether functionalized graphene oxide (GO) bearing two commonly used drugs of lidocaine (LDC) and thalidomide (THD) as an agent for the treatment of neuropathic pain. The sequential drug release of LDC and THD from the developed LDC-THD-GO nanosheets exhibited a synergistic effect on neuropathic pain in vitro and in vivo, as evidenced by the increased pain threshold in mechanical allodynia and hyperalgesic response tests, and the improved inhibition of proinflammatory cytokines TNF-α, IL-1ß, IL-6, and nitric oxide. We believed that the present study herein would hold promise for future development of a new generation of potent agents for neuropathic pain relief.
Asunto(s)
Anestésicos Locales/administración & dosificación , Preparaciones de Acción Retardada/química , Inmunosupresores/administración & dosificación , Lidocaína/administración & dosificación , Neuralgia/tratamiento farmacológico , Talidomida/administración & dosificación , Anestésicos Locales/uso terapéutico , Animales , Células Cultivadas , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Grafito/química , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inmunología , Inmunosupresores/uso terapéutico , Lidocaína/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Neuralgia/inmunología , Óxidos/química , Talidomida/uso terapéuticoRESUMEN
PURPOSE: To investigate the effects of two different inhalation anesthetic expelling methods on emergence agitation in infants following sevoflurane anesthesia. METHODS: 100 infants (1~3 years old) with cleft lip and palate and ASA classification I~II were randomized into two groups, a sevoflurane concentration decreasing expelling group (group n = 50 cases) and a low fresh gas flow expelling group (group D = 50 cases). The operation for cleft lip and palate repair was under general anesthesia, in which 30 minutes after initiation of narcosis ending extubation was indicated and after the tubes were removed the patients were sent to the post-anesthesia care unit (PACU) to record anesthesia times, emergence agitation scores, Ramsay scores and adverse reactions including drowsiness, respiratory depression, nausea and vomiting, chills, hiccough or laryngospasms. RESULTS: There were no differences in anesthesia times, awaking time and time until extubation between the two groups. 10 min after start of expelling sevoflurane, blood pressure and heart rates were higher in group N than in group D (P < 0.05). The postoperative agitation incidence and the degree of agitation were lower in group D than in group N (P < 0.05). CONCLUSION: Postoperative agitation is prone to occur in patients with sevoflurane concentration decreasing expelling. Avoiding sevoflurane application maintenance in the stage of sevoflurane expelling reduces the occurrence of postoperative agitation and diminishes physiological and psychological harm.
RESUMEN
Thalidomide was introduced to the market in 1957 as a sedative and antiemetic agent, and returned to the market for the treatment of myelodysplastic syndrome and multiple myeloma. There are reports and studies of thalidomide as an analgesic or analgesic adjuvant in clinic. However, the underlying mechanism is quite elusive. Many studies suggest that the analgesic effect of thalidomide may be due to its immunomodulatory and anti-inflammatory properties as it suppresses the production of tumor necrosis factor α (TNF-α) selectively. However, it is not clear whether any other mechanisms are implicated in the pain relief. In this study, we demonstrated that the peripheral vanilloid receptor 1 (TRPV1) channel was also involved in the analgesic effect of thalidomide in different cell and animal models. During the activation by its agonist capsaicin, the cation inward influx through TRPV1 channels and the whole-cell current significantly decreased after TRPV1-overexpressed HEK293 cells or dorsal root ganglion (DRG) neurons were pre-treated with thalidomide for 20 minutes. And such attenuation in the TRPV1 activity was in a dose-dependent manner of thalidomide. In an acetic acid writhing test, pre-treatment of thalidomide decreased the writhing number in the wild type mice, while it did not happen in TRPV1 knockout mice, suggesting that the TRPV1 channel was involved in the pain relief by thalidomide. Taken together, the study showed that TRPV1 channels were involved in the analgesic effects of thalidomide. Such alteration in the action of TRPV1 channels by thalidomide may help understand how thalidomide takes analgesic effect in the body in addition to its selective inhibition of TNF-α production.
Asunto(s)
Analgésicos/farmacología , Canales Catiónicos TRPV/fisiología , Talidomida/farmacología , Animales , Ganglios Espinales/efectos de los fármacos , Células HEK293 , Humanos , Ratones , Ratones NoqueadosRESUMEN
The aim of the present study was to determine the expression of p-Akt in ovarian serous carcinoma (OSC) and its association with proliferation and apoptosis. Paraffin-embedded tissues of patients aged between 35 and 64 years old without history of radiotherapy, chemotherapy and hormone therapy prior to surgery were collected. In total, samples included 12 ovarian serous cystadenomas (OSAs), 18 ovarian serous borderline tumors (OS-BTs) and 46 OSCs. Of the 46 OSC samples, 16 were well-differentiated, 20 were moderately differentiated and 10 were poorly differentiated, while 22 developed lymphatic metastases and 24 were metastasis-free. An additional 10 paraffin-embedded normal ovarian tissues (NOTs) were used as controls. Streptavidin-peroxidase immunohistochemistry assays were used to investigate the expression of p-Akt and cyclin D1 in the collected samples. Compared with NOT, p-Akt expression in the OS-BT and OSC groups, as well as cyclin D1 expression in the OSA and OSC groups, was significantly elevated (P<0.05). Compared with the OSA group, p-Akt expression in the OSC group was significantly elevated (P<0.01) and reversely associated with tumor differentiation (P<0.01), whereas cyclin D1 expression showed no correlation with tumor differentiation (P>0.05). The expression of p-Akt, caspase-3 and cyclin D1 was positively associated with lymphatic metastasis (r=0.334; P=0.023). The expression of p-Akt gradually increased with carcinoma development and was associated with differentiation and metastasis of OSC, revealing that the activation of the PI3K/Akt signaling pathway is involved in the development of OSC. Furthermore, the expression of cyclin D1 gradually increased in the NOT, OSA, OS-BT and OSC groups and was associated with tumor metastasis.
RESUMEN
OBJECTIVE: To discuss the experience of combining extra-corporeal membrane oxygenation (ECMO) with intra-aortic balloon pump (IABP) for the treatment of acute heart failure in critically ill adults. METHODS: The clinical data of 54 patients who received ECMO combined with IABP due to acute heart failure between January 2008 and July 2012 were retrospectively analysed. Thirty-eight of the patients were male, and 16 were female; the mean age was 57±11. Thirty-nine of the patients received IABP first but were still unable to maintain adequate circulation, and were then given ECMO; the other 15 underwent ECMO first, but due to increased left ventricular load, the opening of the aortic valve was restricted and IABP was then introduced. RESULTS: Thirty-four patients (63%) were successfully weaned from ECMO; 21 patients (38.9%) survived to discharge. Major complications that occurred were renal failure (27 cases), infection (20 cases), blood plasma leakage in the oxygenator (13 cases), bleeding (18 cases), limb ischaemia (eight cases), and neurological complications (seven cases); in the group of patients who did not survive, the rates of bleeding occurrence, infection and renal failure were markedly higher than in the survived patients group. In both groups, the longer the patients were on support, the more improvement they showed in terms of MAP, CVP, Lac, SvO2 and IS. CONCLUSION: ECMO and IABP may have synergistic effects and play complementary roles in the treatment of acute cardiac failure; with timely administration, active prevention and treatment of complications, they can improve treatment outcome.