RESUMEN
BACKGROUND: The neurosteroid dehydroepiandrosterone sulphate (DHEAS) activates the sigma-1 receptor, inhibits gamma-aminobutyric acid A (GABAA) and glycine receptors, and induces hyperalgesic effects. Although its effects have been studied in various tissues of the nervous system, its synaptic mechanisms in nociceptive pathways remain to be elucidated. METHODS: The threshold of mechanical hypersensitivity and spontaneous pain behaviour was assessed using the von Frey test in adult male Wistar rats after intrathecal administration of DHEAS. We also investigated the effects of DHEAS on synaptic transmission in the spinal dorsal horn using slice patch-clamp electrophysiology. RESULTS: Intrathecally administered DHEAS elicited dose-dependent mechanical hyperalgesia and spontaneous pain behaviours (withdrawal threshold: saline; 51.0 [20.1] g, 3 µg DHEAS; 14.0 [7.8] g, P<0.01, 10 µg DHEAS; 6.9 [5.2] g, 15 min after administration, P<0.001). DHEAS at 100 µM increased the frequency of miniature postsynaptic currents in the rat dorsal spinal horn; this increase was extracellular Ca2+-dependent but not sigma-1 and N-methyl-d-aspartate receptor-dependent. DHEAS suppressed the frequency of miniature inhibitory postsynaptic currents in a GABAA receptor- and sigma-1 receptor-dependent manner. CONCLUSIONS: These results suggest that DHEAS participates in the pathophysiology of nociceptive synaptic transmission in the spinal cord by potentiation of glutamate release and inhibition of the GABAA receptor.
Asunto(s)
Sulfato de Deshidroepiandrosterona/farmacología , Dolor/fisiopatología , Asta Dorsal de la Médula Espinal/fisiopatología , Animales , Modelos Animales de Enfermedad , Masculino , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Transmisión Sináptica/fisiologíaRESUMEN
BACKGROUND: The local anesthetic bupivacaine is thought not only to block sodium channels but also to interact with various receptors. Here, the authors focus on excitatory glutamatergic transmission in the superficial dorsal horn of the spinal cord with respect to its importance for nociceptive processing. METHODS: The effects of bupivacaine on the response to exogenous administration of N-methyl-D-aspartate (NMDA) receptor agonists were examined in lamina II neurons of adult rat spinal cord slices using the whole-cell patch-clamp technique. RESULTS: Bupivacaine (0.5, 2 mm) dose-dependently reduced the peak amplitudes of exogenous NMDA-induced currents. However, this inhibitory effect of bupivacaine (2 mm) was not blocked by the presence of tetrodotoxin, a sodium channel blocker, or La(3+), a voltage-gated Ca+ channel blocker, and was unaffected by changes in pH conditions. Moreover, intrapipette guanosine-5'-O-(2-thiodiphosphate) (1 mm), a G-protein inhibitor, did not block the reduction of NMDA current amplitudes by bupivacaine. Similarly, lidocaine, ropivacaine, and mepivacaine also reduced the amplitudes of NMDA-induced currents. CONCLUSIONS: These findings raise the possibility that the antinociceptive effect of bupivacaine may be due to direct modulation of NMDA receptors in the superficial dorsal horn. In addition to voltage-gated sodium channels, glutamate NMDA receptors are also important for analgesia induced by local anesthetics.
Asunto(s)
Anestésicos Locales/farmacología , Bupivacaína/farmacología , Glutamatos/fisiología , Células del Asta Posterior/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Bloqueadores de los Canales de Calcio/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Proteínas de Unión al GTP/antagonistas & inhibidores , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/fisiología , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Lantano/farmacología , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacologíaRESUMEN
We present a case of profound bradycardia and cardiac arrest in a 61-year-old man, which occurred during left upper lobectomy and lymph node dissection for the ligamentum arteriosum. General anesthesia was maintained by propofol TIVA combined with epidural anesthesia. During the electrocautery dissection of the lymph node of the ligamentum arteriosum the patient became extremely bradycardic for 10 min. Subsequent traction with forceps further aggravated the bradycardia leading to cardiac arrest. In order to continue the procedure, we initiated epicardial pacing and switched to isoflurane anesthesia. Given the close proximity of the lymph node of the ligamentum arteriosum to the thoracic cardiac branch of the vagus nerve and the cardiac plexus, we believe that the observed bradycardia and cardiac arrest are likely attributable to vasovagal stimulation.
Asunto(s)
Anestesia Epidural , Anestesia General , Bradicardia/etiología , Paro Cardíaco/etiología , Cuidados Intraoperatorios , Complicaciones Intraoperatorias/etiología , Neoplasias Pulmonares/cirugía , Escisión del Ganglio Linfático , Neumonectomía , Nervio Vago/fisiopatología , Bradicardia/terapia , Estimulación Cardíaca Artificial , Electrocoagulación , Corazón/inervación , Paro Cardíaco/terapia , Humanos , Isoflurano , Masculino , Persona de Mediana Edad , Pericardio , Propofol , Tórax/inervaciónRESUMEN
Background: Musculoskeletal sarcomas (MSSs) are rare cancers and often aggressive tumors that originate from mesenchymal tissue. Patients with advanced MSS often report difficulties with symptom burden, which can reduce their health-related quality-of-life. Objective: The aim of this study was to describe the patterns of the physical symptoms of MSS patients in the palliative setting and to detail the palliative treatment used in the last two weeks of life. Design: Retrospective study using the electronic patient records from a single institution. Setting/Subjects: A retrospective study was carried out in a sample of 46 consecutive MSS patients with locally advanced/metastatic disease, who were hospitalized and died in our department. The median age of these patients was 56 years at death. Measurements: Symptom burden and medical intervention during the last two weeks of life were collected. Results: The most frequent physical symptoms were pain and dyspnea in 93% and 78% of patients, respectively, while only 17% of patients suffered from nausea. A total of 98% of patients required opioids, and most patients were treated with morphine through either subcutaneous or intravenous continuous injection. Nonsteroidal anti-inflammatory drugs and acetaminophen were administered to 79% of patients. Corticosteroids were administered for the relief of dyspnea to 83% of patients. Of the patients, 46% received palliative chemotherapy within the last two weeks of life, and the oral treatment was continued until a median of 5.6 days before death. In addition, 39% of patients received a sedative treatment during the last two weeks of life for uncontrolled refractory symptoms. Conclusions: The symptom burden experienced by advanced MSS patients is profound at the end of life for all palliative approaches. Therefore, palliative medicine is an important and even crucial component of the continuum of care, allowing for aggressive symptom management with a variety of medical interventions, including palliative sedation.
Asunto(s)
Disnea/tratamiento farmacológico , Hipnóticos y Sedantes/uso terapéutico , Enfermedades Musculoesqueléticas/psicología , Enfermedades Musculoesqueléticas/terapia , Cuidados Paliativos/psicología , Sarcoma/psicología , Sarcoma/terapia , Cuidado Terminal/psicología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Dexmedetomidine is a highly specific, potent and selective alpha(2)-adrenoceptor agonist. Although intrathecal and epidural administration of dexmedetomidine has been found to produce analgesia, whether this analgesia results from an effect on spinal cord substantia gelatinosa (SG) neurons remains unclear. Here, we investigated the effects of dexmedetomidine on postsynaptic transmission in SG neurons of rat spinal cord slices using the whole-cell patch-clamp technique. In 92% of the SG neurons examined (n = 84), bath-applied dexmedetomidine induced outward currents at -70 mV in a concentration-dependent manner, with the value of effective concentration producing a half-maximal response (0.62 microM). The outward currents induced by dexmedetomidine were suppressed by the alpha(2)-adrenoceptor antagonist yohimbine, but not by prazosin, an alpha(1)-, alpha(2B)- and alpha(2C)-adrenoceptor antagonist. Moreover, the dexmedetomidine-induced currents were partially suppressed by the alpha(2C)-adrenoceptor antagonist JP-1302, while simultaneous application of JP-1302 and the alpha(2A)-adrenoceptor antagonist BRL44408 abolished the current completely. The action of dexmedetomidine was mimicked by the alpha(2A)-adrenoceptor agonist oxymetazoline. Plots of the current-voltage relationship revealed a reversal potential at around -86 mV. Dexmedetomidine-induced currents were blocked by the addition of GDP-beta-S [guanosine-5'-O-(2-thiodiphosphate)] or Cs+ to the pipette solution. These findings suggest that dexmedetomidine hyperpolarizes the membrane potentials of SG neurons by G-protein-mediated activation of K+ channels through alpha(2A)- and alpha(2C)-adrenoceptors. This action of dexmedetomidine might contribute, at least in part, to its antinociceptive action in the spinal cord.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Dexmedetomidina/farmacología , Células del Asta Posterior/efectos de los fármacos , Sustancia Gelatinosa/citología , Sustancia Gelatinosa/efectos de los fármacos , Animales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Proteínas de Unión al GTP/metabolismo , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Células del Asta Posterior/fisiología , Canales de Potasio/fisiología , Ratas , Ratas Wistar , Sustancia Gelatinosa/fisiología , Sinapsis/efectos de los fármacos , Sinapsis/fisiologíaRESUMEN
Taurine has been suggested to modulate nociceptive information at the spinal cord level. In this study, the pharmacological properties of taurine were investigated in adult rat substantia gelatinosa (SG) neurons using whole-cell patch-clamp method. We found that taurine seemed to have higher efficacy than glycine on glycine receptors in SG neurons. An increase in chloride conductance was responsible for taurine-induced currents. Taurine at 0.3 mM activated glycine receptors, whereas at 3 mM activated both glycine and gamma-aminobutyric acid A receptors. The currents activated by coapplication of taurine and glycine are cross inhibitive. Altogether these results show that taurine might represent another important neurotransmitter or modulator in SG neurons, which may be involved in antinociception.
Asunto(s)
Agonistas del GABA , Receptores de GABA-A/efectos de los fármacos , Receptores de Glicina/administración & dosificación , Sustancia Gelatinosa/efectos de los fármacos , Taurina/farmacología , Animales , Bicuculina/farmacología , Interpretación Estadística de Datos , Antagonistas del GABA/farmacología , Glicinérgicos/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Estricnina/farmacología , Proteínas tau/metabolismoRESUMEN
We experienced three cases of ventilatory difficulty through a Proseal laryngeal mask airway was encountered during general anesthesia using remifentanil and sevoflurane. General anesthesia was induced with propofol and maintained with remifentanil (0.2-0.25 microg x kg(-1) x min(-1)) and sevoflurane (1-1.5%). Increased airway pressure was noticed suddenly. Initially in cases 1 and 2, we suspected insufficient depth of anesthesia as a cause of this event. However, in case 3, we observed vocal cord closure by fiberoptic bronchoscopy, suggesting that airway obstruction occurred at the level of the glottis. The patient could be easily ventilated after administration of muscle relaxant (suxamethonium). The inability to ventilate patients with opioids has been ascribed to increased thoracic wall rigidity or vocal cord closure or combination of both factors. In our three cases, the closure of vocal cord after remifentanil administration seems to be the major cause of difficult ventilation during general anesthesia. Therefore, supraglottic airway devices should be applied with caution during general anesthesia with remifentanil and sevoflurane without muscle relaxant.
Asunto(s)
Analgésicos Opioides/efectos adversos , Anestesia General , Piperidinas/efectos adversos , Pliegues Vocales/patología , Adulto , Constricción Patológica/inducido químicamente , Femenino , Humanos , Máscaras Laríngeas , Éteres Metílicos , Persona de Mediana Edad , Fármacos Neuromusculares Despolarizantes , Remifentanilo , Sevoflurano , SuccinilcolinaAsunto(s)
Células del Asta Anterior/fisiología , Dinoprostona/fisiología , Dolor/etiología , Antiinflamatorios no Esteroideos/administración & dosificación , Ciclooxigenasa 2 , Humanos , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inyecciones Espinales , Isoenzimas/metabolismo , Proteínas de la Membrana , Dolor/tratamiento farmacológico , Dolor/prevención & control , Prostaglandina-Endoperóxido Sintasas/metabolismo , Transducción de Señal/fisiologíaRESUMEN
The effects of nitrous oxide (N2O) are thought to be mediated by several pharmacological pathways at different levels of the central nervous system. Here, we focus on excitatory glutamatergic transmission in the superficial dorsal horn of the spinal cord with respect to its importance for the nociceptive processing. The effects of 50% N2O on electrically evoked and spontaneous excitatory glutamatergic transmission and on the response to exogenous administration of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid (AMPA) receptor agonists were examined in lamina II neurons of adult rat spinal cord slices using the whole-cell patch-clamp technique. Peak amplitudes of Adelta- and C-fiber evoked monosynaptic NMDA- and AMPA-receptor-mediated excitatory postsynaptic currents (EPSCs) were decreased in the presence of N2O. N2O reduced the peak amplitude and integrated area of exogenous NMDA- and AMPA-induced currents. Moreover N2O changed the distribution of miniature EPSC amplitude, but not frequency distribution in most neurons. N2O inhibits glutamatergic transmission in the superficial dorsal horn by modulating the NMDA- and AMPA-receptors. Our findings raise the possibility that the antinociceptive effect of N2O may be directly mediated at the level of the spinal cord.
Asunto(s)
Ácido Glutámico/fisiología , Inhibición Neural/fisiología , Óxido Nitroso/farmacología , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/fisiología , Transmisión Sináptica/efectos de los fármacos , Animales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , N-Metilaspartato/farmacología , Ratas , Ratas Wistar , Receptores AMPA/agonistas , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
BACKGROUND: Although intrathecal administration of opioids produces antinociceptive effects in the spinal cord, it has not been established whether intrathecal opioid application more effectively terminates C fiber-mediated pain than A fiber-mediated pain. Here, the authors focus on the differences in opioid actions on Adelta- and C-afferent responses. METHODS: Using the whole cell patch clamp technique, the authors investigated the presynaptic inhibitory actions of micro-, delta-, and kappa-opioid receptor agonists on primary afferent-evoked excitatory postsynaptic currents (EPSCs) in substantia gelatinosa neurons of adult rat spinal cord slices. RESULTS: The micro agonist DAMGO (0.1, 1 microM) reduced the amplitude of glutamatergic monosynaptic Adelta- or C fiber-evoked EPSCs. C fiber-evoked EPSCs were inhibited to a greater extent than Adelta fiber-evoked EPSCs. The delta agonist DPDPE (1, 10 microM) produced modest inhibition of Adelta- or C fiber-evoked EPSCs. In contrast, the kappa agonist U69593 (1 microM) did not affect the amplitude of either Adelta or C fiber-evoked EPSCs. CONCLUSIONS: These results indicate that opioids suppress excitatory synaptic transmission mainly through activation of micro receptors on primary afferent C fibers. Given that the substantia gelatinosa is the main termination of Adelta and C fibers transmitting nociceptive information, the current findings may partially explain the different potency of opioid agonists.
Asunto(s)
Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Fibras Nerviosas/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Encefalina Ala(2)-MeFe(4)-Gli(5)/administración & dosificación , Fármacos actuantes sobre Aminoácidos Excitadores/administración & dosificación , Potenciales Postsinápticos Excitadores , Ácido Glutámico , Técnicas In Vitro , Fibras Nerviosas Mielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas , Técnicas de Placa-Clamp , Ratas , Columna Vertebral/efectos de los fármacos , Sustancia Gelatinosa/efectos de los fármacosRESUMEN
BACKGROUND: Although intrathecal administration of midazolam, a water-soluble imidazobenzodiazepine derivative, has been found to produce analgesia, how it exerts this effect at the neuronal level in the spinal cord is not fully understood. METHODS: The effects of midazolam on electrically evoked and spontaneous excitatory transmission were examined in lamina II neurons of adult rat spinal cord slices using the whole cell patch clamp technique. RESULTS: Bath-applied midazolam (1 microm) diminished Adelta- and C-fiber evoked polysynaptic excitatory postsynaptic currents in both amplitude and integrated area. However, it affected neither Adelta- and C-fiber evoked monosynaptic excitatory postsynaptic currents in amplitude nor miniature excitatory postsynaptic currents in amplitude, frequency, and decay time constant. In the presence of a benzodiazepine receptor antagonist, flumazenil (5 microm), midazolam (1 microm) did not diminish Adelta-fiber evoked polysynaptic excitatory postsynaptic currents, suggesting that midazolam modulate the gamma-aminobutyric acid interneurons in the dorsal horn. CONCLUSIONS: Midazolam reduced excitatory synaptic transmission by acting on the gamma-aminobutyric acid type A/benzodiazepine receptor in interneurons, leading to a decrease in the excitability of spinal dorsal horn neurons. This may be a possible mechanism for the antinociception by midazolam in the spinal cord.