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1.
Anesthesiology ; 128(3): 609-619, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29251644

RESUMO

BACKGROUND: Clinical and experimental data show that peripheral nerve blocks last longer in the presence of diabetic neuropathy. This may occur because diabetic nerve fibers are more sensitive to local anesthetics or because the local anesthetic concentration decreases more slowly in the diabetic nerve. The aim of this study was to investigate both hypotheses in a rodent model of neuropathy secondary to type 2 diabetes. METHODS: We performed a series of sciatic nerve block experiments in 25 Zucker Diabetic Fatty rats aged 20 weeks with a neuropathy component confirmed by neurophysiology and control rats. We determined in vivo the minimum local anesthetic dose of lidocaine for sciatic nerve block. To investigate the pharmacokinetic hypothesis, we determined concentrations of radiolabeled (C) lidocaine up to 90 min after administration. Last, dorsal root ganglia were excised for patch clamp measurements of sodium channel activity. RESULTS: First, in vivo minimum local anesthetic dose of lidocaine for sciatic nerve motor block was significantly lower in diabetic (0.9%) as compared to control rats (1.4%). Second, at 60 min after nerve block, intraneural lidocaine was higher in the diabetic animals. Third, single cell measurements showed a lower inhibitory concentration of lidocaine for blocking sodium currents in neuropathic as compared to control neurons. CONCLUSIONS: We demonstrate increased sensitivity of the diabetic neuropathic nerve toward local anesthetics, and prolonged residence time of local anesthetics in the diabetic neuropathic nerve. In this rodent model of neuropathy, both pharmacodynamic and pharmacokinetic mechanisms contribute to prolonged nerve block duration.


Assuntos
Anestésicos Locais/farmacologia , Neuropatias Diabéticas , Lidocaína/farmacologia , Bloqueio Nervoso/métodos , Animais , Modelos Animais de Doenças , Masculino , Ratos , Nervo Isquiático/efeitos dos fármacos
2.
Minerva Anestesiol ; 83(2): 183-190, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27834474

RESUMO

BACKGROUND: Saphenous nerve block contributes to analgesia after knee and lower leg surgery. However, literature reports a wide range of volumes of local anesthetic being used for this block. METHODS: A non-randomized controlled trial in a single university hospital in March 2015. Eighteen healthy volunteers (ASA 1 status, aged 27-43 years; male-to-female ratio 11/7) were needed to determine the minimum local anesthetic volume (MLAV) of mepivacaine 2% using the Dixon up-and-down method to achieve a selective ultrasound-guided saphenous nerve block. The primary endpoint MLAV (ED50 and ED95) for an ultrasound-guided saphenous nerve block were determined. The secondary endpoints were the position of the saphenous nerve, block onset and duration of action, cutaneous spread of the block, and the occurrence of femoral nerve motor block. RESULTS: The measured MLAV dose that was effective in 50% of cases (ED50) for a complete saphenous nerve block was 1.5 mL; the calculated MLAV dose for 95% of cases (ED95) was 1.9 mL. The saphenous nerve was encountered in almost all cases on the anterior/anteromedial aspect of the femoral artery. We found no correlation between local anesthetic volume and the onset or duration of the block. Cutaneous spread of the nerve block was observed on the anteromedial aspect of the lower leg, with considerable individual variation between individuals in the study. No femoral motor block was observed. CONCLUSIONS: For a selective ultrasound-guided saphenous nerve block, the ED95 MLAV of mepivacaine 2% is 1.9 mL.


Assuntos
Anestésicos Locais/administração & dosagem , Mepivacaína/administração & dosagem , Bloqueio Nervoso/métodos , Veia Safena , Adulto , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Masculino , Ultrassonografia de Intervenção
3.
Injury ; 46(9): 1738-42, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26068645

RESUMO

AIMS: Selected patients in traumatic cardiac arrest may benefit from pre-hospital thoracotomy. Pre-hospital care physicians rarely have surgical training and the procedure is rarely performed in most European systems. Limited data exists to inform teaching and training for this procedure. We set out to run a pilot study to determine the time required to perform a thoracotomy and the a priori defined complication rate. METHODS: We adapted an existing system operating procedure requiring four instruments (Plaster-of-Paris shears, dressing scissors, non-toothed forceps, scalpel) for this study. We identified a convenience sample of surgically trained and non-surgically trained participants. All received a training package including a lecture, practical demonstration and cadaver experience. Time to perform the procedure, anatomical accuracy and a priori complication rates were assessed. RESULTS: The mean total time for the clamshell thoracotomy from thoracic incision to delivery of the heart was 167 s (02:47 min:sec). There was no statistical difference in the time to complete the procedure or complication rate among surgeons, non-surgeons and students. The complication rate dropped from 36% in the first attempt to 7% in the second attempt but this was not statistically significant. This is a pilot study and small numbers of participants arguably saw it underpowered to define differences between study groups. CONCLUSION: Clamshell thoracotomy can be taught using cadaver models. In this simulated environment, the procedure may be performed rapidly with minimum equipment.


Assuntos
Tamponamento Cardíaco/terapia , Serviços Médicos de Emergência/métodos , Medicina de Emergência/educação , Parada Cardíaca/terapia , Massagem Cardíaca/métodos , Ressuscitação/educação , Toracotomia/educação , Cadáver , Feminino , Humanos , Internato e Residência , Masculino , Duração da Cirurgia , Projetos Piloto , Ressuscitação/métodos , Toracotomia/métodos
4.
J Physiol ; 591(4): 1111-31, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23148321

RESUMO

The T-junction of sensory neurons in the dorsal root ganglion (DRG) is a potential impediment to action potential (AP) propagation towards the CNS. Using intracellular recordings from rat DRG neuronal somata during stimulation of the dorsal root, we determined that the maximal rate at which all of 20 APs in a train could successfully transit the T-junction (following frequency) was lowest in C-type units, followed by A-type units with inflected descending limbs of the AP, and highest in A-type units without inflections. In C-type units, following frequency was slower than the rate at which AP trains could be produced in either dorsal root axonal segments or in the soma alone, indicating that the T-junction is a site that acts as a low-pass filter for AP propagation. Following frequency was slower for a train of 20 APs than for two, indicating that a cumulative process leads to propagation failure. Propagation failure was accompanied by diminished somatic membrane input resistance, and was enhanced when Ca(2+)-sensitive K(+) currents were augmented or when Ca(2+)-sensitive Cl(-) currents were blocked. After peripheral nerve injury, following frequencies were increased in axotomized C-type neurons and decreased in axotomized non-inflected A-type neurons. These findings reveal that the T-junction in sensory neurons is a regulator of afferent impulse traffic. Diminished filtering of AP trains at the T-junction of C-type neurons with axotomized peripheral processes could enhance the transmission of activity that is ectopically triggered in a neuroma or the neuronal soma, possibly contributing to pain generation.


Assuntos
Potenciais de Ação/fisiologia , Células Receptoras Sensoriais/fisiologia , Nervos Espinhais/lesões , Nervos Espinhais/fisiopatologia , Animais , Comportamento Animal , Gânglios Espinais/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley
5.
Resuscitation ; 82(9): 1198-201, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21621893

RESUMO

BACKGROUND AND AIM OF THE STUDY: Arterial lines are widely used in operating rooms, critical care and emergency departments. Although invasive arterial blood pressure monitoring and arterial blood gas analysis are prehospitally available, the use of arterial lines in the field remains an exception. This study evaluates the feasibility, indications and therapeutic consequences of prehospital arterial line insertion. METHODS: Prospective observational study in four physician-staffed emergency medical systems (EMS), documenting patient status, indications, location of puncture, number of tries and time for puncture and therapeutic consequences. RESULTS: During the one-year observation period, arterial line placement succeeded in 115 (83.9%) of 137 patients. The median time for successful arterial cannulation was 2 min (IQR 1, 3 min; range: 30-600s), for preparing the invasive blood pressure monitoring 3 min (IQR 2, 4 min, range: 30-600s). Main indications were cardiopulmonary resuscitation (36.5%), post-resuscitation care (16.8%), respiratory insufficiency (24.1%) and unconsciousness (22.6%). Therapeutic consequences depended on whether the EMS was equipped with a blood gas analyzer or not and were, overall, reported in 51.3% of patients: fluids, vasoactive or antihypertensive therapy, correction of ventilation or acidosis. No complications occurred during the prehospital phase. CONCLUSION: The insertion of arterial lines is feasible under prehospital conditions, without delaying or complicating patient care. Indications originating from intrahospital use are also valid in the field. In particular when combined with arterial blood gas measurement, the use of arterial lines often leads to important therapeutic consequences.


Assuntos
Cateteres de Demora/estatística & dados numéricos , Competência Clínica , Serviços Médicos de Emergência/métodos , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/terapia , Adulto , Idoso , Áustria , Gasometria , Reanimação Cardiopulmonar/métodos , Reanimação Cardiopulmonar/mortalidade , Tratamento de Emergência/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/diagnóstico , Médicos/provisão & distribuição , Estudos Prospectivos , Taxa de Sobrevida , Gestão da Qualidade Total , Resultado do Tratamento
6.
Pain ; 152(2): 274-284, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20943317

RESUMO

Nociception modulates heart rate (HR) and mean arterial pressure (MAP), suggesting their use of HR and MAP as indicators of pain in animals. We explored this with telemetric recording in unrestrained control and neuropathic (spinal nerve ligation) rats. Plantar stimulation was performed emulating techniques commonly used to measure pain, specifically brush stroke, von Frey fiber application, noxious pin stimulation, acetone for cooling, and radiant heating, while recording MAP, HR, and specific evoked somatomotor behaviors (none; simple withdrawal; or sustained lifting, shaking, and grooming representing hyperalgesia). Pin produced elevations in both HR and MAP, and greater responses accompanied hyperalgesia behavior compared to simple withdrawal. Von Frey stimulation depressed MAP, and increased HR only when stimulation produced hyperalgesia behavior, suggesting that minimal nociception occurs without this behavior. Brush increased MAP even when no movement was evoked. Cold elevated both HR and MAP whether or not there was withdrawal, but MAP increased more when withdrawal was triggered. Heating, consistently depressed HR and MAP, independent of behavior. Other than a greater HR response to pin in animals made hyperalgesic by injury, cardiovascular events evoked by stimulation did not differ between control and neuropathic animals. We conclude that (a) thermoregulation rather than pain may dominate responses to heat and cooling stimuli; (b) brush and cooling stimuli may be perceived and produce cardiovascular activation without nocifensive withdrawal; (c) sensations that produce hyperalgesia behavior are accompanied by greater cardiovascular activation than those producing simple withdrawal; and (d) von Frey stimulation lacks cardiovascular evidence of nociception except when hyperalgesia behavior is evoked.


Assuntos
Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Neuralgia/etiologia , Medição da Dor/métodos , Animais , Procedimentos Cirúrgicos Dermatológicos , Modelos Animais de Doenças , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Hiperalgesia/cirurgia , Ligadura/efeitos adversos , Masculino , Neuralgia/fisiopatologia , Neuralgia/cirurgia , Ratos , Ratos Sprague-Dawley , Pele/fisiopatologia , Vigília/fisiologia
7.
Anesthesiology ; 113(1): 134-46, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20526180

RESUMO

BACKGROUND: Ca is the dominant second messenger in primary sensory neurons. In addition, disrupted Ca signaling is a prominent feature in pain models involving peripheral nerve injury. Standard cytoplasmic Ca recording techniques use high K or field stimulation and dissociated neurons. To compare findings in intact dorsal root ganglia, we used a method of simultaneous electrophysiologic and microfluorimetric recording. METHODS: Dissociated neurons were loaded by bath-applied Fura-2-AM and subjected to field stimulation. Alternatively, we adapted a technique in which neuronal somata of intact ganglia were loaded with Fura-2 through an intracellular microelectrode that provided simultaneous membrane potential recording during activation by action potentials (APs) conducted from attached dorsal roots. RESULTS: Field stimulation at levels necessary to activate neurons generated bath pH changes through electrolysis and failed to predictably drive neurons with AP trains. In the intact ganglion technique, single APs produced measurable Ca transients that were fourfold larger in presumed nociceptive C-type neurons than in nonnociceptive Abeta-type neurons. Unitary Ca transients summated during AP trains, forming transients with amplitudes that were highly dependent on stimulation frequency. Each neuron was tuned to a preferred frequency at which transient amplitude was maximal. Transients predominantly exhibited monoexponential recovery and had sustained plateaus during recovery only with trains of more than 100 APs. Nerve injury decreased Ca transients in C-type neurons, but increased transients in Abeta-type neurons. CONCLUSIONS: Refined observation of Ca signaling is possible through natural activation by conducted APs in undissociated sensory neurons and reveals features distinct to neuronal types and injury state.


Assuntos
Sinalização do Cálcio , Gânglios Espinais/lesões , Gânglios Espinais/metabolismo , Células Receptoras Sensoriais/metabolismo , Potenciais de Ação , Animais , Bloqueadores dos Canais de Cálcio , Canais de Cálcio , Citofotometria/métodos , Fura-2/administração & dosagem , Fura-2/análogos & derivados , Concentração de Íons de Hidrogênio , Masculino , Potenciais da Membrana , Fibras Nervosas , Neurônios Aferentes , Ratos , Ratos Sprague-Dawley
9.
Pain ; 146(3): 293-300, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19729245

RESUMO

The baroreceptor reflex buffers autonomic changes by decreasing sympathetic activity and increasing vagal activity in response to blood pressure elevations, and by the reverse actions when the blood pressure falls. Because of the many bidirectional interactions of pain and autonomic function, we investigated the effect of painful nerve injury by spinal nerve ligation (SNL) on heart rate (HR), blood pressure (BP) and their regulation by the baroreceptor reflex. Rats receiving SNL were separated into either a hyperalgesic group that developed sustained lifting, shaking and grooming of the foot after plantar punctate nociceptive stimulation by pin touch or a group of animals that failed to show this hyperalgesic behavior after SNL. SNL produced no effect on resting BP recorded telemetrically in unrestrained rats compared to control rats receiving either skin incision or sham SNL. However, two tests of baroreceptor gain showed depression only in animals that developed sustained hyperalgesia after SNL. The animals that failed to develop hyperalgesia after SNL were found to have elevations in HR both before and for the first 4 days after SNL, and HR variability analysis gave indications of decreased vagal control of resting HR and elevated sympatho-vagal balance at these same time intervals. In human patients, other research has shown that blunted baroreceptor reflex sensitivity predicts poor outcome during conditions such as hypertension, congestive heart failure, myocardial infarction, and stroke. If baroreceptor reflex suppression is also found in human subjects during chronic neuropathic pain, this may adversely affect survival.


Assuntos
Barorreflexo/fisiologia , Hiperalgesia/fisiopatologia , Hiperalgesia/psicologia , Nervos Espinhais/lesões , Animais , Comportamento Animal/fisiologia , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Ligadura , Masculino , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Descanso , Telemetria , Vasoconstritores/farmacologia
10.
Anesthesiology ; 111(2): 393-405, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19602957

RESUMO

BACKGROUND: Painful nerve injury leads to disrupted Ca signaling in primary sensory neurons, including decreased endoplasmic reticulum (ER) Ca storage. This study examines potential causes and functional consequences of Ca store limitation after injury. METHODS: Neurons were dissociated from axotomized fifth lumbar (L5) and the adjacent L4 dorsal root ganglia after L5 spinal nerve ligation that produced hyperalgesia, and they were compared to neurons from control animals. Intracellular Ca levels were measured with Fura-2 microfluorometry, and ER was labeled with probes or antibodies. Ultrastructural morphology was analyzed by electron microscopy of nondissociated dorsal root ganglia, and intracellular electrophysiological recordings were obtained from intact ganglia. RESULTS: Live neuron staining with BODIPY FL-X thapsigargin (Invitrogen, Carlsbad, CA) revealed a 40% decrease in sarco-endoplasmic reticulum Ca-ATPase binding in axotomized L5 neurons and a 34% decrease in L4 neurons. Immunocytochemical labeling for the ER Ca-binding protein calreticulin was unaffected by injury. Total length of ER profiles in electron micrographs was reduced by 53% in small axotomized L5 neurons, but it was increased in L4 neurons. Cisternal stacks of ER and aggregation of ribosomes occurred less frequently in axotomized neurons. Ca-induced Ca release, examined by microfluorometry with dantrolene, was eliminated in axotomized neurons. Pharmacologic blockade of Ca-induced Ca release with dantrolene produced hyperexcitability in control neurons, confirming its functional importance. CONCLUSIONS: After axotomy, ER Ca stores are reduced by anatomic loss and possibly diminished sarco-endoplasmic reticulum Ca-ATPase. The resulting disruption of Ca-induced Ca release and protein synthesis may contribute to the generation of neuropathic pain.


Assuntos
Cálcio/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Compostos de Boro , Calbindina 2 , Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Dantroleno/farmacologia , Eletrofisiologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Corantes Fluorescentes , Hiperalgesia/patologia , Imuno-Histoquímica , Ligadura , Masculino , Microscopia Eletrônica , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteína G de Ligação ao Cálcio S100/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/ultraestrutura , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/metabolismo , Nervos Espinhais/ultraestrutura
11.
Anesthesiology ; 111(2): 381-92, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19602958

RESUMO

BACKGROUND: The cellular mechanisms of neuropathic pain are inadequately understood. Previous investigations have revealed disrupted Ca signaling in primary sensory neurons after injury. The authors examined the effect of injury on intracellular Ca stores of the endoplasmic reticulum, which critically regulate the Ca signal and neuronal function. METHODS: Intracellular Ca levels were measured with Fura-2 or mag-Fura-2 microfluorometry in axotomized fifth lumbar (L5) dorsal root ganglion neurons and adjacent L4 neurons isolated from hyperalgesic rats after L5 spinal nerve ligation, compared to neurons from control animals. RESULTS: Endoplasmic reticulum Ca stores released by the ryanodine-receptor agonist caffeine decreased by 46% in axotomized small neurons. This effect persisted in Ca-free bath solution, which removes the contribution of store-operated membrane Ca channels, and after blockade of the mitochondrial, sarco-endoplasmic Ca-ATPase and the plasma membrane Ca ATPase pathways. Ca released by the sarco-endoplasmic Ca-ATPase blocker thapsigargin and by the Ca-ionophore ionomycin was also diminished by 25% and 41%, respectively. In contrast to control neurons, Ca stores in axotomized neurons were not expanded by neuronal activation by K depolarization, and the proportionate rate of refilling by sarco-endoplasmic Ca-ATPase was normal. Luminal Ca concentration was also reduced by 38% in axotomized neurons in permeabilized neurons. The adjacent neurons of the L4 dorsal root ganglia showed modest and inconsistent changes after L5 spinal nerve ligation. CONCLUSIONS: Painful nerve injury leads to diminished releasable endoplasmic reticulum Ca stores and a reduced luminal Ca concentration. Depletion of Ca stores may contribute to the pathogenesis of neuropathic pain.


Assuntos
Axotomia , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Animais , Axônios/patologia , Cafeína/farmacologia , Capsaicina/farmacologia , Células Cultivadas , Estimulantes do Sistema Nervoso Central/farmacologia , Retículo Endoplasmático/fisiologia , Hiperalgesia/patologia , Ionomicina/farmacologia , Ligadura , Masculino , Degeneração Neural/patologia , Medição da Dor , Ratos , Ratos Sprague-Dawley , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Nervo Isquiático/lesões , Nervos Espinhais/lesões , Tapsigargina/farmacologia
12.
Anesth Analg ; 107(3): 1045-51, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18713927

RESUMO

BACKGROUND: We have previously shown that a decrease of inward Ca(2+) flux (I(Ca)) across the sensory neuron plasmalemma, such as happens after axotomy, increases neuronal excitability. From this, we predicted that increasing I(Ca) in injured neurons should correct their hyperexcitability. METHODS: The influence of increased or decreased I(Ca) upon membrane biophysical variables and excitability was determined during recording from A-type neurons in nondissociated dorsal root ganglia after spinal nerve ligation using an intracellular recording technique. RESULTS: When the bath Ca(2+) level was increased to promote I(Ca), the after-hyperpolarization was decreased and repetitive firing was suppressed, which also followed amplification of Ca(2+)-activated K(+) current with selective agents NS1619 and NS309. A decreased external bath Ca(2+) concentration had the opposite effects, similar to previous observations in uninjured neurons. CONCLUSIONS: These findings indicate that at least a part of the hyperexcitability of somatic sensory neurons after axotomy is attributable to diminished inward Ca(2+) flux, and that measures to restore I(Ca) may potentially be therapeutic for painful peripheral neuropathy.


Assuntos
Cálcio/metabolismo , Gânglios Espinais/embriologia , Neurônios/metabolismo , Animais , Comportamento Animal , Benzimidazóis/farmacologia , Cálcio/química , Indóis/farmacologia , Masculino , Modelos Biológicos , Neurônios Aferentes/metabolismo , Oximas/farmacologia , Potássio/química , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/patologia
13.
Anesthesiology ; 109(3): 473-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18719445

RESUMO

BACKGROUND: Little is known regarding the final needle tip location when various intensities of nerve stimulation are used to guide block needle insertion. Therefore, in control and hyperglycemic dogs, the authors examined whether lower-intensity stimulation results in injection closer to the sciatic nerve than higher-threshold stimulation. METHODS: During anesthesia, the sciatic nerve was approached with an insulated nerve block needle emitting either 1 mA (high-current group, n = 9) or 0.5 mA (low-current group, n = 9 in control dogs and n = 6 in hyperglycemic dogs). After positioning to obtain a distal motor response, the lowest current producing a response was identified, and ink (0.5 ml) was injected. Frozen sections of the tissue revealed whether the ink was in contact with the epineurium of the nerve, distant to it, or within it. RESULTS: In control dogs, the patterns of distribution using high-threshold (final current 0.99 +/- 0.03 mA, mean +/- SD) and low-threshold (final current 0.33 +/- 0.08 mA) stimulation equally showed ink that was in contact with the epineurium or distant to it. One needle placement in the high-threshold group resulted in intraneural injection. In hyperglycemic dogs, all needle insertions used a low-threshold technique (n = 6, final threshold 0.35 +/- 0.08 mA), and all resulted in intraneural injections. CONCLUSIONS: In normal dogs, current stimulation levels in the range of 0.33-1.0 mA result in needle placement comparably close to the sciatic nerve but do not correlate with distance from the target nerve. In this experimental design, low-threshold electrical stimulation does not offer satisfactory protection against intraneural injection in the presence of hyperglycemia.


Assuntos
Corantes/administração & dosagem , Estimulação Elétrica/métodos , Hiperglicemia/fisiopatologia , Agulhas , Nervo Isquiático/fisiopatologia , Animais , Corantes/farmacocinética , Modelos Animais de Doenças , Cães , Modelos Animais , Nervos Periféricos/fisiologia , Nervos Periféricos/fisiopatologia , Projetos Piloto , Distribuição Aleatória , Nervo Isquiático/fisiologia
14.
Anesth Analg ; 107(2): 673-85, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18633052

RESUMO

BACKGROUND: Chronic neuropathic pain resulting from neuronal damage remains difficult to treat, in part, because of incomplete understanding of underlying cellular mechanisms. We have previously shown that inward Ca2+ flux (I(Ca)) across the sensory neuron plasmalemma is decreased in a rodent model of chronic neuropathic pain, but the direct consequence of this loss of I(Ca) on function of the sensory neuron has not been defined. We therefore examined the extent to which altered membrane properties after nerve injury, especially increased excitability that may contribute to chronic pain, are attributable to diminished Ca2+ entry. METHODS: Intracellular microelectrode measurements were obtained from A-type neurons of dorsal root ganglia excised from uninjured rats. Recording conditions were varied to suppress or promote I(Ca) while biophysical variables and excitability were determined. RESULTS: Both lowered external bath Ca2+ concentration and blockade of I(Ca) with bath cadmium diminished the duration and area of the after-hyperpolarization (AHP), accompanied by decreased current threshold for action potential (AP) initiation and increased repetitive firing during sustained depolarization. Reciprocally, elevated bath Ca2+ increased the AHP and suppressed repetitive firing. Voltage sag during neuronal hyperpolarization, indicative of the cation-nonselective H-current, diminished with decreased bath Ca2+, cadmium application, or chelation of intracellular Ca2+. Additional recordings with selective blockers of I(Ca) subtypes showed that N-, P/Q, L-, and R-type currents each contribute to generation of the AHP and that blockade of any of these, and the T-type current, slows the AP upstroke, prolongs the AP duration, and (except for L-type current) decreases the current threshold for AP initiation. CONCLUSIONS: Taken together, our findings show that suppression of I(Ca) decreases the AHP, reduces the hyperpolarization-induced voltage sag, and increases excitability in sensory neurons, replicating changes that follow peripheral nerve trauma. This suggests that the loss of I(Ca) previously demonstrated in injured sensory neurons contributes to their dysfunction and hyperexcitability, and may lead to neuropathic pain.


Assuntos
Cálcio/metabolismo , Gânglios Espinais/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Cádmio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Quelantes/farmacologia , Ácido Edético/farmacologia , Eletrofisiologia , Técnicas In Vitro , Masculino , Neurônios Aferentes/metabolismo , Ratos , Ratos Sprague-Dawley
15.
Pain ; 136(1-2): 188-201, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18316160

RESUMO

Hindlimb pain models developed in rats have been transposed to mice, but assumed sciatic nerve neuroanatomic similarities have not been examined. We compared sciatic nerve structural organization in mouse strains (C57BL/6J, DBA/2J, and B6129PF2/J) and rat strains (Wistar, Brown Norway, and Sprague-Dawley). Dissection and retrograde labeling showed mouse sciatic nerve origins predominantly from the third lumbar (L3) and L4 spinal nerves, unlike the L4 and L5 in rats. Proportionate contributions by each level differed significantly between strains in both mice and rats. Whereas all rats had six lumbar vertebrae, variable patterns in mice included mostly five vertebrae in DBA/2J, mostly six vertebrae in C57BL/6J, and a mix in B6129PF2/J. Mice with a short lumbar vertebral column showed a rostral shift in relative contributions to the sciatic nerve by L3 and L4. Ligation of the mouse L4 nerve created hyperalgesia similar to that in rats after L5 ligation, and motor changes were similar after mouse L4 and rat L5 ligation (foot cupping) and after mouse L3 and rat L4 ligation (flexion weakness). Thus, mouse L3 and L4 neural segments are anatomically and functionally homologous with rat L4 and L5 segments. Neuronal changes after distal injury or inflammation should be sought in the mouse L3 and L4 ganglia, and the spinal nerve ligation model in mice should involve ligation of the L4 nerve while L3 remains intact. Strain-dependent variability in segmental contributions to the sciatic nerve may account in part for genetic differences in pain behavior after spinal nerve ligation.


Assuntos
Dor/genética , Dor/patologia , Nervo Isquiático/anatomia & histologia , Neuropatia Ciática/genética , Neuropatia Ciática/patologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Ratos , Ratos Endogâmicos BN , Ratos Sprague-Dawley , Ratos Wistar , Nervo Isquiático/fisiologia , Especificidade da Espécie
16.
Anesthesiology ; 107(1): 117-27, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17585223

RESUMO

BACKGROUND: Although the activation-induced intracellular Ca signal is disrupted by sensory neuron injury, the contribution of specific Ca channel subtypes is unknown. METHODS: Transients in dissociated rat dorsal root ganglion neurons were recorded using fura-2 microfluorometry. Neurons from control rats and from neuropathic animals after spinal nerve ligation were activated either by elevated bath K or by field stimulation. Transients were compared before and after application of selective blockers of voltage-activated Ca channel subtypes. RESULTS: Transient amplitude and area were decreased by blockade of the L-type channel, particularly during sustained K stimulation. Significant contributions to the Ca transient are attributable to the N-, P/Q-, and R-type channels, especially in small neurons. Results for T-type blockade varied widely between cells. After injury, transients lost sensitivity to N-type and R-type blockers in axotomized small neurons, whereas adjacent small neurons showed decreased responses to blockers of R-type channels. Axotomized large neurons were less sensitive to blockade of N- and P/Q-type channels. After injury, neurons adjacent to axotomy show decreased sensitivity of K-induced transients to L-type blockade but increased sensitivity during field stimulation. CONCLUSIONS: All high-voltage-activated Ca current subtypes contribute to Ca transients in sensory neurons, although the L-type channel contributes predominantly during prolonged activation. Injury shifts the relative contribution of various Ca channel subtypes to the intracellular Ca transient induced by neuronal activation. Because this effect is cell-size specific, selective therapies might potentially be devised to differentially alter excitability of nociceptive and low-threshold sensory neurons.


Assuntos
Canais de Cálcio/fisiologia , Sinalização do Cálcio/fisiologia , Neurônios Aferentes/fisiologia , Traumatismos dos Nervos Periféricos , Nervos Espinhais/lesões , Animais , Comportamento Animal/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Separação Celular , Tamanho Celular , Células Cultivadas , Citofotometria , Eletrofisiologia , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/fisiopatologia , Hiperalgesia/psicologia , Ligadura , Masculino , Fibras Nervosas/fisiologia , Neurônios Aferentes/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Degeneração Walleriana/fisiopatologia
17.
Anesthesiology ; 107(1): 106-16, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17585222

RESUMO

BACKGROUND: Neuropathic pain is inadequately treated and poorly understood at the cellular level. Because intracellular Ca signaling critically regulates diverse neuronal functions, the authors examined effects of peripheral nerve injury on the Ca transient that follows neuronal activation. METHODS: Cytoplasmic Ca levels were recorded by digital microfluorometry from dissociated dorsal root ganglion neurons of hyperalgesic animals after ligation of the fifth lumbar spinal nerve and control animals. Neurons were activated by field stimulation or by K depolarization. RESULTS: Transients in presumptively nociceptive, small, capsaicin-sensitive neurons were diminished after axotomy, whereas transient amplitude increased in axotomized nonnociceptive neurons. Axotomy diminished the upward shift in resting calcium after transient recovery. In contrast, nociceptive neurons adjacent to axotomy acquired increased duration of the transient and greater baseline shift after K activation. Transients of nonnociceptive neurons adjacent to axotomy showed no changes after injury. In nociceptive neurons from injured rats that did not develop hyperalgesia, transient amplitude and baseline offset were large after axotomy, whereas transient duration in the adjacent neurons was shorter compared with neurons excised from hyperalgesic animals, which show normalization of these features. CONCLUSIONS: A diminished Ca signal in axotomized neurons may be in part due to loss of Ca influx through voltage-gated Ca channels. The upward shift in resting Ca level after activation, which is diminished after axotomy in presumed nociceptive neurons, is a previously unrecognized aspect of neuronal plasticity. These changes in the critical Ca signal may mediate various injury-related abnormalities in Ca-dependent neuronal.


Assuntos
Axotomia , Sinalização do Cálcio/fisiologia , Neurônios Aferentes/fisiologia , Traumatismos dos Nervos Periféricos , Animais , Capsaicina/farmacologia , Tamanho Celular , Citofotometria , Estimulação Elétrica , Gânglios Espinais/fisiologia , Hiperalgesia/fisiopatologia , Ligadura , Masculino , Fibras Nervosas/fisiologia , Nociceptores/efeitos dos fármacos , Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/lesões , Estimulação Química , Degeneração Walleriana/fisiopatologia
18.
Brain Res ; 1132(1): 84-99, 2007 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-17184741

RESUMO

UNLABELLED: Calcium-activated potassium channels regulate AHP and excitability in neurons. Since we have previously shown that axotomy decreases I(Ca) in DRG neurons, we investigated the association between I(Ca) and K((Ca)) currents in control medium-sized (30-39 microM) neurons, as well as axotomized L5 or adjacent L4 DRG neurons from hyperalgesic rats following L5 SNL. Currents in response to AP waveform voltage commands were recorded first in Tyrode's solution and sequentially after: 1) blocking Na(+) current with NMDG and TTX; 2) addition of K((Ca)) blockers with a combination of apamin 1 microM, iberiotoxin 200 nM, and clotrimazole 500 nM; 3) blocking remaining K(+) current with the addition of 4-AP, TEA-Cl, and glibenclamide; and 4) blocking I(Ca) with cadmium. In separate experiments, currents were evoked (HP -60 mV, 200 ms square command pulses from -100 to +50 mV) while ensuring high levels of activation of I(K(Ca)) by clamping cytosolic Ca(2+) concentration with pipette solution in which Ca(2+) was buffered to 1 microM. This revealed I(K(Ca)) with components sensitive to apamin, clotrimazole and iberiotoxin. SNL decreases total I(K(Ca)) in axotomized (L5) neurons, but increases total I(K(Ca)) in adjacent (L4) DRG neurons. All I(K(Ca)) subtypes are decreased by axotomy, but iberiotoxin-sensitive and clotrimazole-sensitive current densities are increased in adjacent L4 neurons after SNL. In an additional set of experiments we found that small-sized control DRG neurons also expressed iberiotoxin-sensitive currents, which are reduced in both axotomized (L5) and adjacent (L4) neurons. CONCLUSIONS: Axotomy decreases I(K(Ca)) due to a direct effect on K((Ca)) channels. Axotomy-induced loss of I(Ca) may further potentiate current reduction. This reduction in I(K(Ca)) may contribute to elevated excitability after axotomy. Adjacent neurons (L4 after SNL) exhibit increased I(K(Ca)) current.


Assuntos
Gânglios Espinais/metabolismo , Neurônios Aferentes/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Canais de Potássio Cálcio-Ativados/metabolismo , Neuropatia Ciática/metabolismo , Animais , Axotomia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Gânglios Espinais/citologia , Gânglios Espinais/fisiopatologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Ligadura , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neurônios Aferentes/citologia , Neurônios Aferentes/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Doenças do Sistema Nervoso Periférico/fisiopatologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/fisiopatologia , Bloqueadores dos Canais de Sódio/farmacologia
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