RESUMEN
Previous studies by our group have shown that peripheral inflammatory insult, using the lambda-carrageenan inflammatory pain (CIP) model, induced alterations in the molecular and functional properties of the blood-brain barrier (BBB). The question remained whether these changes were mediated via an inflammatory and/or neuronal mechanism. In this study, we investigated the involvement of neuronal input from pain activity on alterations in BBB integrity by peripheral inhibition of nociceptive input. A perineural injection of 0.75% bupivacaine into the right hind leg prior to CIP was used for peripheral nerve block. Upon nerve block, there was a significant decrease in thermal allodynia induced by CIP, but no effect on edema formation 1 h post-CIP. BBB permeability was increased 1 h post-CIP treatment as determined by in situ brain perfusion of [(14)C] sucrose; bupivacaine nerve block of CIP caused an attenuation of [(14)C] sucrose permeability, back to saline control levels. Paralleling the changes in [(14)C] sucrose permeability, we also report increased expression of three tight junction (TJ) proteins, zonula occluden-1 (ZO-1), occludin and claudin-5 with CIP. Upon bupivacaine nerve block, changes in expression were prevented. These data show that the lambda-carrageenan-induced changes in [(14)C] sucrose permeability and protein expression of ZO-1, occludin and claudin-5 are prevented with inhibition of nociceptive input. Therefore, we suggest that nociceptive signaling is in part responsible for the alteration in BBB integrity under CIP.
Asunto(s)
Barrera Hematoencefálica/fisiopatología , Edema Encefálico/fisiopatología , Inflamación/fisiopatología , Nociceptores/efectos de los fármacos , Dolor/fisiopatología , Células Receptoras Sensoriales/fisiopatología , Anestésicos Locales/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Edema Encefálico/etiología , Bupivacaína/farmacología , Carragenina/antagonistas & inhibidores , Claudina-5 , Modelos Animales de Enfermedad , Hiperalgesia/complicaciones , Hiperalgesia/fisiopatología , Inflamación/inducido químicamente , Inflamación/complicaciones , Proteínas de la Membrana/metabolismo , Bloqueo Nervioso/métodos , Ocludina , Dolor/complicaciones , Fosfoproteínas/metabolismo , Ratas , Células Receptoras Sensoriales/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sacarosa/farmacocinética , Uniones Estrechas/metabolismo , Proteína de la Zonula Occludens-1RESUMEN
BACKGROUND: Distal neuropathy is part of the clinical phenotype in most males with the fragile X-associated tremor/ataxia syndrome (FXTAS) caused by the 55 to 200 CGG repeat expansion. METHODS: We performed nerve conduction studies in 16 male carriers with FXTAS, 11 non-FXTAS carriers, and 11 control subjects and assessed the outcomes with respect to the fragile X mental retardation 1 genotype (FMR1) (Online Mendelian Inheritance in Man [OMIM] 309550; NT011681) and messenger RNA expression. RESULTS: Men with FXTAS had slower tibial nerve conduction velocities and prolonged F-wave latencies compared with controls (z = 2.06, P = .04; and z = 2.73, P = .005) and unaffected premutation males (z = 1.98, P = .04; and z = 2.00, P = .04). Compound muscle action potential amplitudes were smaller in the FXTAS group relative to controls. Sural nerve action potential amplitudes were reduced in the FXTAS group compared with controls. After controlling for age, there was a significant relationship between the longer CGG repeat number and tibial nerve conduction velocity slowing (r = -0.42, P = .04) and between elevated messenger RNA levels and reduction of the tibial compound muscle action potential velocity (r = -0.52, P = .01) in the permutation group. CONCLUSIONS: Male premutation carriers had significant conduction abnormalities of motor and sensory nerves that correlated with molecular measures, suggesting that the premutation FMR1 genotype is a causal factor. There was also evidence of nerve conduction abnormalities in non-FXTAS carriers compared with controls, which suggests that the neuropathy can occur without the full clinical presentation of FXTAS.
Asunto(s)
Análisis Mutacional de ADN , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Tamización de Portadores Genéticos , Conducción Nerviosa/genética , Conducción Nerviosa/fisiología , Degeneraciones Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/fisiopatología , Temblor/genética , Temblor/fisiopatología , Potenciales de Acción/genética , Potenciales de Acción/fisiología , Anciano , Electromiografía , Síndrome del Cromosoma X Frágil/diagnóstico , Genotipo , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Masculino , Persona de Mediana Edad , Neuronas Motoras/fisiología , Músculos/inervación , ARN Mensajero/genética , Tiempo de Reacción/genética , Tiempo de Reacción/fisiología , Células Receptoras Sensoriales/fisiopatología , Degeneraciones Espinocerebelosas/diagnóstico , Nervio Sural/fisiopatología , Nervio Tibial/fisiopatología , Temblor/diagnóstico , Repeticiones de TrinucleótidosRESUMEN
BACKGROUND: An appropriate bedside test for small fiber neuropathy does not exist so far. Cold hypaesthesia occurs as an early onset symptom, and the new handheld device NeuroQuick (NQ) was recently claimed to be a valid and reliable screening tool for its quantitative assessment. AIMS: Comparison of the NQ with standardized quantitative sensory testing (QST) in patients suffering from chronic painful dysaesthesia with and without pathological cold detection threshold (CDT). METHODS: Forty-one patients with and without diabetes mellitus displaying chronic painful dysaesthesia were included (18 men, 55.8+/-13 years). According to the German network protocol QST was performed in the body area with the severest symptoms and at the opposite side as control after thorough clinical-neurological examination. The NeuroQuick, developed as quantitative bedside testing of cold thermal perception based on the wind chill, was used subsequently. RESULTS: DT was pathologically increased in 14 and within normal range in 27 patients; NQ values were pathological in 9 and non-pathological in 32 patients. Thus NQ obtained 7.4% false positive and 50% false negative results in detecting cold hypaesthesia, corresponding to 92.6% specificity, 50% sensitivity and a positive and negative predictive value of 78%, respectively. CONCLUSIONS: This study demonstrates that the NeuroQuick is not an adequate screening device for cold hypaesthesia in patients with chronic neuropathic pain. It exhibits a high specificity but only low sensitivity in the identification of such small fiber dysfunction; a reliable and valid screening tool should necessarily provide opposite features.
Asunto(s)
Frío , Hipoestesia/diagnóstico , Fibras Nerviosas , Examen Neurológico/métodos , Nervios Periféricos/fisiopatología , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Adulto , Anciano , Enfermedad Crónica , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/fisiopatología , Femenino , Humanos , Hipoestesia/fisiopatología , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Fibras Nerviosas Amielínicas , Neuralgia/diagnóstico , Neuralgia/fisiopatología , Dimensión del Dolor/métodos , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Sistemas de Atención de Punto , Valor Predictivo de las Pruebas , Células Receptoras Sensoriales/fisiopatología , Sensación TérmicaRESUMEN
UNLABELLED: The toxicity profile of oxaliplatin, a platinum derivative currently used in the treatment of colorectal cancer, differs from those of the other platinum compounds, cisplatin and carboplatin. Oxaliplatin treatment induces an acute neurotoxicity characterized by a rapid onset of cold-induced distal dysesthesia and a chronic sensory peripheral neuropathy. A single intravenous dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia and heat and cold allodynia; repeated administration intensified symptoms. A single intradermal dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia. A single dose intravenous oxaliplatin also lowered thresholds and increased responses of C-fiber nociceptors to mechanical stimulation, confirming a peripheral site of action. Whereas peripheral administration of inhibitors of second messengers implicated in models of other painful peripheral neuropathies (PKA, PKC, NO, Ca(2+), and caspase) had no effect; both systemic and local administration of antioxidants (acetyl-L-carnitine, alpha-lipoic acid or vitamin C), all markedly inhibited oxaliplatin-induced hyperalgesia. Intrathecal administration of the neurotoxin for IB4-positive nociceptors, IB4-saporin, markedly attenuated IB4 staining in the dorsal horn of the spinal cord and completely prevented oxaliplatin-induced hyperalgesia. We suggest that oxaliplatin acts on IB4 (+)-nociceptors to induce oxidative stress-dependent acute peripheral sensory neuropathy. PERSPECTIVE: Many drugs used to treat cancer produce pain as their dose-limiting side effect. We used a model of this pain syndrome induced by oxaliplatin to demonstrate that pain is produced by action on a subset of nociceptors, the IB4-positive DRG neurons. This information could help define cellular targets against which protective therapies could be developed.
Asunto(s)
Neuralgia/inducido químicamente , Nociceptores/efectos de los fármacos , Compuestos Organoplatinos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Células Receptoras Sensoriales/efectos de los fármacos , Enfermedad Aguda , Animales , Antineoplásicos/toxicidad , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Inyecciones Intravenosas , Inyecciones Subcutáneas , Lectinas/farmacología , Masculino , Fibras Nerviosas Amielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas/fisiología , Neuralgia/metabolismo , Neuralgia/fisiopatología , Nociceptores/metabolismo , Oxaliplatino , Estrés Oxidativo/fisiología , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Lectinas de Plantas , Ratas , Proteínas Inactivadoras de Ribosomas Tipo 1/farmacología , Saporinas , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/fisiopatología , Coloración y EtiquetadoRESUMEN
The sensory deficit in TrkB deficient mice was evaluated by counting the neuronal loss in lumbar dorsal root ganglia (DRG), the absence of sensory receptors (cutaneous--associated to the hairy and glabrous skin - muscular and articular), and the percentage and size of the neurocalcin-positive DRG neurons (a calcium-binding protein which labels proprioceptive and mechanoceptive neurons). Mice lacking TrkB lost 32% of neurons, corresponding to the intermediate-sized and neurocalcin-positive ones. This neuronal lost was accomplished by the absence of Meissner corpuscles, and reduction of hair follicle-associated sensory nerve endings and Merkel cells. The mutation was without effect on Pacinian corpuscles, Golgi's organs and muscle spindles. Present results further characterize the sensory deficit of the TrkB-/- mice demonstrating that the intermediate-sized neurons in lumbar DRG, as well as the cutaneous rapidly and slowly adapting sensory receptors connected to them, are under the control of TrkB for survival and differentiation. This study might serve as a baseline for future studies in experimentally induced neuropathies affecting TrkB positive DRG neurons and their peripheral targets, and to use TrkB ligands in the treatment of neuropathies in which cutaneous mechanoreceptors are primarily involved.
Asunto(s)
Ganglios Espinales/metabolismo , Mecanorreceptores/metabolismo , Neuronas Aferentes/metabolismo , Enfermedades del Sistema Nervioso Periférico/metabolismo , Receptor trkB/deficiencia , Trastornos Somatosensoriales/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Tamaño de la Célula , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Ganglios Espinales/citología , Ganglios Espinales/fisiopatología , Inmunohistoquímica , Mecanorreceptores/fisiopatología , Células de Merkel/metabolismo , Ratones , Ratones Noqueados , Factores de Crecimiento Nervioso/metabolismo , Neurocalcina/metabolismo , Neuronas Aferentes/citología , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Propiocepción/genética , Receptor trkB/genética , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/fisiopatología , Trastornos Somatosensoriales/genética , Trastornos Somatosensoriales/fisiopatología , Tacto/genéticaRESUMEN
Repetitive transcranial magnetic stimulation over the primary motor cortex (M1) was recently introduced to modulate pain perception. The aim of this double-blind cross-over study was to investigate the effect of a modified rTMS paradigm, called cTBS on experimentally induced laser-evoked pain applied over the left M1. cTBS inhibits the cortical excitability of the M1 for approximately 1 h. Subjective pain was measured using the verbal analogue scale prior to, immediately after and 30 min post-stimulation. cTBS, and not the sham stimulation resulted in a significant decrease in pain perception on both hands, accentuated on the right hand. Further studies are needed using motor cortex TBS in chronic pain to pave the way towards a therapeutic tool.
Asunto(s)
Corteza Motora/efectos de la radiación , Nociceptores/efectos de la radiación , Manejo del Dolor , Ritmo Teta , Estimulación Magnética Transcraneal/métodos , Adolescente , Adulto , Enfermedad Crónica/terapia , Estudios Cruzados , Método Doble Ciego , Lateralidad Funcional/fisiología , Mano/inervación , Mano/fisiopatología , Humanos , Rayos Láser , Corteza Motora/fisiología , Inhibición Neural/fisiología , Inhibición Neural/efectos de la radiación , Nociceptores/fisiología , Dolor/etiología , Dolor/fisiopatología , Dimensión del Dolor , Umbral del Dolor/fisiología , Umbral del Dolor/efectos de la radiación , Tiempo de Reacción/fisiología , Tiempo de Reacción/efectos de la radiación , Células Receptoras Sensoriales/fisiopatología , Piel/inervación , Piel/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate whether subjects with palmar hyperhidrosis have functional problems with the handgrip caused by the wet slippery surface of palm and fingertips. We used two different dosages of botulinum toxin to explore its impact on sweating and on muscle strength in the hand. METHOD: Using an object equipped with force sensors we measured the muscle strength and calculated the coefficients of friction and safety margin (SM) in the precision grip before and 2, 4, 6, 8 10-12 weeks and 6 months after treatment of 13 patients with two different doses of botulinum toxin. Sweat evaporation was measured simultaneously. RESULTS: A significant decrease in evaporation and a parallel reduction of grip force in the dominant hand of the patients were observed. The SM used by the patients was significantly lower after the treatment, and increased gradually when sweating reappeared. CONCLUSION: These measurements showed, for the first time, that hyperhidrosis of the palms may cause an objective perturbation of the hand function which may be partially corrected by botulinum toxin treatment.
Asunto(s)
Fuerza de la Mano , Hiperhidrosis/complicaciones , Trastornos del Movimiento/fisiopatología , Trastornos de la Sensación/fisiopatología , Adolescente , Adulto , Antidiscinéticos/farmacología , Antidiscinéticos/uso terapéutico , Toxinas Botulínicas/farmacología , Toxinas Botulínicas/uso terapéutico , Femenino , Dedos/inervación , Dedos/fisiopatología , Fricción , Humanos , Hiperhidrosis/tratamiento farmacológico , Hiperhidrosis/fisiopatología , Masculino , Mecanorreceptores , Persona de Mediana Edad , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/etiología , Fuerza Muscular/efectos de los fármacos , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/etiología , Debilidad Muscular/fisiopatología , Propiocepción/efectos de los fármacos , Seguridad , Trastornos de la Sensación/tratamiento farmacológico , Trastornos de la Sensación/etiología , Células Receptoras Sensoriales/fisiopatología , Tacto , Resultado del TratamientoRESUMEN
Metabotropic glutamate 5 receptor (mGluR5) antagonists are effective in animal models of inflammatory and neuropathic pain. The involvement of mGluR5 in visceral pain pathways from the gastrointestinal tract is as yet unknown. We evaluated effects of mGluR5 antagonists on the colorectal distension (CRD)-evoked visceromotor (VMR) and cardiovascular responses in conscious rats, and on mechanosensory responses of mouse colorectal afferents in vitro. Sprague-Dawley rats were subjected to repeated, isobaric CRD (12 x 80 mmHg, for 30s with 5 min intervals). The VMR and cardiovascular responses to CRD were monitored. The mGluR5 antagonists MPEP (1-10 micromol/kg, i.v.) and MTEP (1-3 micromol/kg, i.v.) reduced the VMR to CRD dose-dependently with maximal inhibition of 52+/-8% (p<0.01) and 25+/-11% (p<0.05), respectively, without affecting colonic compliance. MPEP (10 micromol/kg, i.v.) reduced CRD-evoked increases in blood pressure and heart rate by 33+/-9% (p<0.01) and 35+/-8% (p<0.05), respectively. Single afferent recordings were made from mouse pelvic and splanchnic nerves of colorectal mechanoreceptors. Circumferential stretch (0-5 g force) elicited slowly-adapting excitation of action potentials in pelvic distension-sensitive afferents. This response was reduced 55-78% by 10 microM MTEP (p<0.05). Colonic probing (2g von Frey hair) activated serosal splanchnic afferents; their responses were reduced 50% by 10 microM MTEP (p<0.01). We conclude that mGluR5 antagonists inhibit CRD-evoked VMR and cardiovascular changes in conscious rats, through an effect, at least in part, at peripheral afferent endings. Thus, mGluR5 participates in mediating mechanically evoked visceral nociception in the gastrointestinal tract.
Asunto(s)
Tracto Gastrointestinal/fisiopatología , Nociceptores/fisiopatología , Dolor/fisiopatología , Receptores de Glutamato Metabotrópico/metabolismo , Aferentes Viscerales/fisiopatología , Animales , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Colon/inervación , Colon/metabolismo , Colon/fisiopatología , Modelos Animales de Enfermedad , Sistema Nervioso Entérico/efectos de los fármacos , Sistema Nervioso Entérico/metabolismo , Sistema Nervioso Entérico/fisiopatología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Tracto Gastrointestinal/inervación , Tracto Gastrointestinal/metabolismo , Masculino , Mecanorreceptores/efectos de los fármacos , Mecanorreceptores/metabolismo , Ratones , Ratones Endogámicos C57BL , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Dolor/metabolismo , Peristaltismo/efectos de los fármacos , Peristaltismo/fisiología , Estimulación Física/efectos adversos , Presión/efectos adversos , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/fisiopatología , Nervios Esplácnicos/efectos de los fármacos , Nervios Esplácnicos/metabolismo , Nervios Esplácnicos/fisiopatología , Aferentes Viscerales/efectos de los fármacos , Aferentes Viscerales/metabolismoRESUMEN
BACKGROUND: Mast cells (MCs) and nerves can induce cutaneous inflammatory responses, both independently and by interacting with each other. However, little is known about the role of skin nerves and neuropeptides in the regulation of MC-mediated skin inflammation, and the contribution of MCs in neurogenic inflammation is still controversial. OBJECTIVE: The aim of this study was to investigate the effects of cutaneous sensory nerves on MC-driven inflammatory responses. METHODS: Passive cutaneous anaphylaxis, a model for type I allergic skin responses, was studied in the presence or absence of sensory nerves by using a murine model of selective cutaneous denervation. RESULTS: Passive cutaneous anaphylaxis was significantly impaired in the absence of sensory nerves. This effect was not a result of an alteration of mast cell numbers in denervated skin. Moreover, IgE-mediated activation of mast cells was markedly decreased in denervated compared with normal skin. Notably, pretreatment of mice with selective antagonists of the neuropeptides substance P and/or calcitonin gene-related peptide also resulted in decreased inflammatory responses after MC activation. CONCLUSION: These data suggest that sensory skin nerves augment MC-driven inflammatory responses by releasing neuropeptides that increase MC degranulation.
Asunto(s)
Mastocitos/patología , Células Receptoras Sensoriales/fisiopatología , Piel/inervación , Animales , Péptido Relacionado con Gen de Calcitonina/fisiología , Comunicación Celular/genética , Comunicación Celular/inmunología , Desnervación , Inflamación/inmunología , Inflamación/patología , Inflamación/fisiopatología , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Neuroinmunomodulación/genética , Células Receptoras Sensoriales/inmunología , Células Receptoras Sensoriales/patología , Transducción de Señal/genética , Transducción de Señal/inmunología , Piel/inmunología , Piel/patología , Sustancia P/fisiologíaRESUMEN
OBJECTIVE: To develop and validate a questionnaire for assessing cutaneous allodynia (CA), and to estimate the prevalence and severity of CA in the migraine population. METHODS: Migraineurs (n = 11,388) completed the Allodynia Symptom Checklist, assessing the frequency of allodynia symptoms during headache. Response options were never (0), rarely (0), less than 50% of the time (1), > or = 50% of the time (2), and none (0). We used item response theory to explore how well each item discriminated CA. The relations of CA to headache features were examined. RESULTS: All 12 questions had excellent item properties. The greatest discrimination occurred with CA during "taking a shower" (discrimination = 2.54), wearing a necklace (2.39) or ring (2.31), and exposure to heat (2.1) or cold (2.0). The factor analysis demonstrated three factors: thermal, mechanical static, and mechanical dynamic. Based on the psychometrics, we developed a scale distinguishing no CA (scores 0-2), mild (3-5), moderate (6-8), and severe (> or = 9). The prevalence of allodynia among migraineurs was 63.2%. Severe CA occurred in 20.4% of migraineurs. CA was associated with migraine defining features (eg, unilateral pain: odds ratio, 2.3; 95% confidence interval, 2.0-2.4; throbbing pain: odds ratio, 2.3; 95% confidence interval, 2.1-2.6; nausea: odds ratio, 2.3; 95% confidence interval, 2.1-2.6), as well as illness duration, attack frequency, and disability. INTERPRETATION: The Allodynia Symptom Checklist measures overall allodynia and subtypes. CA affects 63% of migraineurs in the population and is associated with frequency, severity, disability, and associated symptoms of migraine. CA maps onto migraine biology.
Asunto(s)
Hiperalgesia/epidemiología , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/epidemiología , Nociceptores/fisiopatología , Dimensión del Dolor/métodos , Umbral del Dolor/fisiología , Adolescente , Adulto , Anciano , Biomarcadores/análisis , Estudios de Cohortes , Comorbilidad , Interpretación Estadística de Datos , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Humanos , Hiperalgesia/fisiopatología , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/fisiopatología , Valor Predictivo de las Pruebas , Pronóstico , Células Receptoras Sensoriales/fisiopatología , Índice de Severidad de la Enfermedad , Piel/inervación , Piel/fisiopatología , Encuestas y CuestionariosRESUMEN
Chronic pruritus of any origin is a frequent discomfort in daily medical practice, and its therapy is challenging. Frequently, the underlying origin may not be identified and symptomatic therapy is necessary. Conventional treatment modalities such as antihistamines often lack efficacy, and hence new therapeutic strategies are necessary. The neuronal mechanisms underlying chronic pruritus have been partly identified during the past years and offer new therapeutic strategies. For example, mast cell degranulation, activation of neuroreceptors on sensory nerve fibres and neurogenic inflammation have been identified to be involved in induction and chronification of the symptom. Accordingly, controlling neuroreceptors such as cannabinoid receptors by agonists or antagonists showed high antipruritic efficacy. Pruritus is transmitted to the central nervous system by specialized nerve fibres and sensory receptors. It has been demonstrated that pruritus and pain have their own neuronal pathways with broad interactions. Accordingly, classical analgesics for neuropathic pain (gabapentin, antidepressants) also exhibit antipruritic efficacy upon clinical use. In summary, these recent developments show that highlighting the basis of pruritus offers modern neurophysiological and neurochemical therapeutic models and the possibility to treat patients with refractory itching of different origin.
Asunto(s)
Antipruriginosos/uso terapéutico , Fármacos del Sistema Nervioso Central/uso terapéutico , Prurito/tratamiento farmacológico , Células Receptoras Sensoriales/fisiopatología , Piel/fisiopatología , Animales , Fármacos Dermatológicos/uso terapéutico , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Prurito/clasificación , Prurito/fisiopatología , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/fisiología , Piel/efectos de los fármacos , Fenómenos Fisiológicos de la PielRESUMEN
Spinal cord stimulation (SCS) is a widely used clinical technique to treat ischemic pain in peripheral, cardiac and cerebral vascular diseases. The use of this treatment advanced rapidly during the late 80's and 90's, particularly in Europe. Although the clinical benefits of SCS are clear and the success rate remains high, the mechanisms are not yet completely understood. SCS at lumbar spinal segments (L2-L3) produces vasodilation in the lower limbs and feet which is mediated by antidromic activation of sensory fibers and decreased sympathetic outflow. SCS at thoracic spinal segments (T1-T2) induces several benefits including pain relief, reduction in both frequency and severity of angina attacks, and reduced short-acting nitrate intake. The benefits to the heart are not likely due to an increase, or redistribution of local blood flow, rather, they are associated with SCS-induced myocardial protection and normalization of the intrinsic cardiac nervous system. At somewhat lower cervical levels (C3-C6), SCS induces increased blood flow in the upper extremities. SCS at the upper cervical spinal segments (C1-C2) increased cerebral blood flow, which is associated with a decrease in sympathetic activity, an increase in vasomotor center activity and a release of neurohumoral factors. This review will summarize the basic science studies that have contributed to our understanding about mechanisms through which SCS produces beneficial effects when used in the treatment of vascular diseases. Furthermore, this review will particularly focus on the antidromic mechanisms of SCS-induced vasodilation in the lower limbs and feet.
Asunto(s)
Terapia por Estimulación Eléctrica/métodos , Isquemia/fisiopatología , Isquemia/terapia , Dolor Intratable/fisiopatología , Dolor Intratable/terapia , Médula Espinal/fisiopatología , Animales , Vasos Sanguíneos/inervación , Vasos Sanguíneos/fisiopatología , Isquemia Encefálica/fisiopatología , Isquemia Encefálica/terapia , Humanos , Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/terapia , Dolor Intratable/etiología , Células Receptoras Sensoriales/fisiopatología , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
We have previously shown that the extracellular signal-regulated kinase (ERK) is activated in the rostral ventromedial medulla (RVM) during peripheral inflammation. In the present study, the relationship between ERK signaling in the RVM and pain hypersensitivity was investigated in the rat. Microinjection of U0126, a mitogen-activated protein kinase kinase inhibitor, into the RVM decreased phosphorylated ERK at 7 h after complete Freund's adjuvant (CFA) injection into the hindpaw. The U0126 microinjection also attenuated thermal hyperalgesia in the ipsilateral hindpaw at 24 h after CFA injection. The ipsilateral paw withdrawal latency in the U0126 group (67.9%+/-5.3% vs. baseline, n=7) was significantly longer than that in the control group (52.0%+/-3.6% vs. baseline, n=8). These findings suggest that activation of ERK in the RVM contributes to thermal hyperalgesia during peripheral inflammation.
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Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hiperalgesia/fisiopatología , Inflamación/fisiopatología , Nervios Periféricos/fisiopatología , Formación Reticular/enzimología , Animales , Vías Eferentes/efectos de los fármacos , Vías Eferentes/enzimología , Vías Eferentes/fisiopatología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Adyuvante de Freund , Miembro Posterior/fisiopatología , Hiperalgesia/inducido químicamente , Inflamación/inducido químicamente , Masculino , Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/enzimología , Bulbo Raquídeo/fisiopatología , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Reflejo/efectos de los fármacos , Reflejo/fisiología , Formación Reticular/efectos de los fármacos , Formación Reticular/fisiopatología , Células Receptoras Sensoriales/fisiopatologíaRESUMEN
In this prospective study, intraepidermal nerve fiber densities (IENFD) and subepidermal nerve plexus densities (SENPD) were quantified by immunostaining in skin punch biopsies from the distal calf in 99 patients with clinical symptoms of painful sensory neuropathy and from 37 age-matched healthy volunteers. The clinical diagnosis was based on history and abnormal thermal thresholds on quantitative sensory testing (QST). In patients with neuropathy, IENFD and SENPD were reduced to about 50% of controls. Elevated warm detection thresholds on QST correlated with IENFD but not with SENPD. Using receiver-operating characteristic (ROC) curve analysis of IENFD values, the diagnostic sensitivity for detecting neuropathy was 0.80 and the specificity 0.82. For SENPD, sensitivity was 0.81 and specificity 0.88. With ROC analysis of both IENFD and SENPD together, the diagnostic sensitivity was further improved to 0.92. The combined examination of IENFD and SENPD is a highly sensitive and specific diagnostic tool in patients suspected to suffer from painful sensory neuropathies but with normal values on clinical neurophysiological studies.
Asunto(s)
Epidermis/inervación , Epidermis/patología , Neuralgia/patología , Enfermedades del Sistema Nervioso Periférico/patología , Células Receptoras Sensoriales/patología , Adulto , Vías Aferentes/patología , Vías Aferentes/fisiopatología , Anciano , Anciano de 80 o más Años , Biopsia , Epidermis/fisiopatología , Femenino , Humanos , Hiperalgesia/etiología , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Masculino , Persona de Mediana Edad , Neuralgia/fisiopatología , Nociceptores/patología , Nociceptores/fisiopatología , Umbral del Dolor/fisiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Curva ROC , Sensibilidad y Especificidad , Células Receptoras Sensoriales/fisiopatologíaRESUMEN
The prolonged use of linezolid, a new antibiotic against drug-resistant gram-positive pathogens, might cause painful neuropathy. This finding raises the possibility that small-diameter sensory nerves in the skin, which are responsible for transmitting nociceptive information, might be affected. We report a 53-year-old female who developed pure small-fibre painful neuropathy (visual analogue scale, VAS = 82 on 0-100 scale) with marked skin denervation in the leg (epidermal nerve density, END = 2.32 fibres/mm, norm <5.88 fibres/mm) and significant elevation of the warm threshold in the foot (40.0 degrees C, norm <39.4 degrees C) after the use of linezolid for 6 months. Eight months after the discontinuation of linezolid, the skin became fully reinnervated (END = 9.04 fibres/mm), with disappearance of neuropathic pain (VAS = 0) and normalisation of the warm threshold (36.3 degrees C). Nerve conduction studies for large-diameter motor and sensory nerves were normal. This report documents a pure small-fibre sensory neuropathy after prolonged use of linezolid, and the relationship between skin innervation and corresponding neuropathic pain.
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Acetamidas/efectos adversos , Antiinfecciosos/efectos adversos , Oxazolidinonas/efectos adversos , Dolor/inducido químicamente , Dolor/fisiopatología , Células Receptoras Sensoriales/efectos de los fármacos , Piel/efectos de los fármacos , Piel/inervación , Acetamidas/uso terapéutico , Antiinfecciosos/uso terapéutico , Biopsia , Epidermis/efectos de los fármacos , Epidermis/inervación , Epidermis/patología , Femenino , Humanos , Linezolid , Persona de Mediana Edad , Conducción Nerviosa/efectos de los fármacos , Oxazolidinonas/uso terapéutico , Dolor/diagnóstico , Células Receptoras Sensoriales/fisiopatología , Piel/patología , Infecciones Estreptocócicas/tratamiento farmacológico , Factores de TiempoRESUMEN
Tolerance to the anti-nociceptive effects of opioids develops rapidly in animals. In contrast, humans with chronic pain show little or no loss of pain relief in prospective opioid trials of 4-8 weeks duration. Employing the Brief Thermal Sensitization model to induce transient cutaneous secondary hyperalgesia, we tested the hypothesis that opioid analgesic tolerance would develop rapidly. In this outpatient randomized placebo-controlled study, subjects in the MMMMP group received two injections of subcutaneous morphine 6 mg (150 min apart) on Monday-Thursday (total 48 mg over 4 days) and matching saline placebo on Friday. Subjects in the PPPPM group received placebo on Monday-Thursday and morphine (total 12 mg) on Friday. Sixty-one healthy volunteers were enrolled; morphine side effects accounted for all nine non-completions. Compared to the first placebo day, the reduction in the area of secondary hyperalgesia on the first morphine day was significant and robust in both groups. Morphine suppression of the painfulness of skin heating and elevation of the heat pain detection threshold were also significant. During 4 days of twice-daily injections, the decline in anti-hyperalgesic effects of morphine did not reach statistical significance (p=0.06) compared to placebo. Morphine side effects did not correlate with anti-hyperalgesic effects and withdrawal symptoms did not emerge. As 4 days is the threshold for demonstrating analgesic tolerance to twice-daily morphine in animal models, a longer period of opioid exposure in healthy volunteers might be needed to detect analgesic tolerance.
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Analgesia/métodos , Analgésicos Opioides/administración & dosificación , Tolerancia a Medicamentos/fisiología , Morfina/administración & dosificación , Dolor/tratamiento farmacológico , Adulto , Analgésicos Opioides/efectos adversos , Esquema de Medicación , Femenino , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Morfina/efectos adversos , Nociceptores/efectos de los fármacos , Nociceptores/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Efecto Placebo , Placebos , Valores de Referencia , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/fisiopatología , Síndrome de Abstinencia a Sustancias/fisiopatología , Factores de TiempoRESUMEN
O nervo infra-orbital está freqüentemente envolvido em fraturas do complexo órbito-zigomático, o que resulta, tanto na fase aguda do traumatismo quanto tardiamente, em alteração da sensibilidade no território cutâneo inervado por ele. A lesão nervosa ocorre por trauma direto, compressão, isquemia ou lacerações nos vários pontos de seu trajeto. Com o objetivo de avaliar as alterações tardias da sensibilidade no território cutâneo do nervo infra-orbital em vítimas de fraturas do complexo órbito-zigomático, foram incluídos no estudo 25 pacientes com fraturas unilaterais do complexo (9 mulheres e 16 homens). O tipo de fratura mais freqüente no grupo em estudo foi o tipo 3 da classificação de Knighte North. Oitenta por cento dos pacientes foram submetidos a tratamento que, em sua grande maioria, cosistiu de exploração cirúrgica e fixação dos focos de fratura com fio de aço ou miniplacas e parafusos. Quando houve necessidade, o assoalho da órbita foi explorado, o conteúdo orbital foi reduzido para a cavidade orbital e o enxerto de cartilagem ou osso autógeno foi colocado. todos os pacientes foram abordados em um período pós-traumatismo de, no mínimo, 24 meses. A avaliação da sensibilidade baseou-se no estudo das fibras de adaptção lenta e das fibras de adaptação rápida do grupo A beta no território do nervo infra-orbital e foi realizada de três maneiras: a) determinação da distância para discriminação de dois pontos; b) determinação do limiar cutâneo de pressão; c) questionamento ao paciente quanto a alterações da sensibilidade local percebidas no seu dia-adia (sensação subjetiva). O lado da face contralateral, onde não ocorreu fratura, foi usado como grupo controle. Observou-se diferença estatisticamente significante entre o lado fraturado e o lado controle nos testes de discriminação de dois pontos e na aferição do limiar cutâneo de pressão para um ponto dinâmico. Observou-se ainda quando inquirido a respeito da sensibilidade de sua face.
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Humanos , Traumatismos Faciales , Cara/inervación , Sensación , Umbral Sensorial , Células Receptoras Sensoriales/fisiopatología , CigomaRESUMEN
OBJECTIVES: Laryngopharyngeal sensory discrimination threshold (LPSDT) testing is a method used to detect sensory deficits in patients in whom swallowing disorders are suspected. LPSDTs have been used to stratify patient risk status with regard to aspiration and to guide dietary management. The aim of this pilot study was to evaluate the intraobserver and interobserver reliability of LPSDT testing among a group of examiners with differing levels of testing experience. METHODS: Twenty-seven healthy volunteers were enrolled in the study to elicit LPSDTs for intraobserver and interobserver reliability measurements. The examiners represented 3 levels of testing experience: an attending laryngologist, a laryngology fellow, and an otolaryngology resident. With the examiners blinded to test results, each subject was examined twice by one examiner and once by a different examiner in an alternating fashion. RESULTS: Six subjects were unable to tolerate the examinations because of coughing and gagging. Spearman rank correlations revealed strong intraobserver reliability for the experienced endoscopists (ie, attending and fellow) but poor reliability for the novice endoscopist (ie, resident). Poor interobserver reliability regardless of endoscopy experience was found. Eighteen percent of the participants demonstrated LPSDTs of more than 4.0 mm Hg (above normal). CONCLUSIONS: 1) Intraobserver reliability was good for experienced endoscopists. 2) Interobserver LPSDT agreement between endoscopists was poor. 3) Eighteen percent of the subjects demonstrated elevated LPSDT thresholds of more than 4 mm Hg.
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Trastornos de Deglución/etiología , Laringe/fisiopatología , Neuronas Motoras/fisiología , Faringe/inervación , Células Receptoras Sensoriales/fisiopatología , Adulto , Deglución/fisiología , Trastornos de Deglución/fisiopatología , Femenino , Humanos , Nervios Laríngeos/fisiopatología , Masculino , Variaciones Dependientes del Observador , Faringe/fisiopatología , Estimulación Física , Valor Predictivo de las Pruebas , Valores de Referencia , Reflejo/fisiología , Aspiración Respiratoria/fisiopatología , Aspiración Respiratoria/prevención & control , Factores de Riesgo , Umbral Sensorial/fisiología , Pliegues Vocales/inervación , Pliegues Vocales/fisiopatologíaRESUMEN
BACKGROUND: Sensory input is crucial to the initiation and modulation of swallowing. From a clinical point of view, oropharyngeal sensory deficits have been shown to be an important cause of dysphagia and aspiration in stroke patients. In the present study we therefore investigated effects of functional oropharyngeal disruption on the cortical control of swallowing. We employed whole-head MEG to study cortical activity during self-paced volitional swallowing with and without topical oropharyngeal anesthesia in ten healthy subjects. A simple swallowing screening-test confirmed that anesthesia caused swallowing difficulties with decreased swallowing speed and reduced volume per swallow in all subjects investigated. Data were analyzed by means of synthetic aperture magnetometry (SAM) and the group analysis of the individual SAM data was performed using a permutation test. RESULTS: The analysis of normal swallowing revealed bilateral activation of the mid-lateral primary sensorimotor cortex. Oropharyngeal anesthesia led to a pronounced decrease of both sensory and motor activation. CONCLUSION: Our results suggest that a short-term decrease in oropharyngeal sensory input impedes the cortical control of swallowing. Apart from diminished sensory activity, a reduced activation of the primary motor cortex was found. These findings facilitate our understanding of the pathophysiology of dysphagia.
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Trastornos de Deglución/etiología , Corteza Motora/fisiopatología , Boca/fisiopatología , Faringe/fisiopatología , Trastornos de la Sensación/complicaciones , Corteza Somatosensorial/fisiopatología , Adulto , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiopatología , Anestésicos Locales/efectos adversos , Deglución/efectos de los fármacos , Deglución/fisiología , Trastornos de Deglución/fisiopatología , Vías Eferentes/fisiología , Potenciales Evocados/fisiología , Femenino , Lateralidad Funcional/fisiología , Humanos , Magnetoencefalografía , Masculino , Persona de Mediana Edad , Boca/inervación , Músculo Esquelético/inervación , Músculo Esquelético/fisiopatología , Faringe/inervación , Trastornos de la Sensación/inducido químicamente , Trastornos de la Sensación/fisiopatología , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/fisiopatologíaRESUMEN
Monitoring the course of diabetic peripheral neuropathy (DPN) remains a challenge. Besides clinical examination, nerve conduction studies (NCS) and quantitative sensory testing (QST) are the most commonly used methods for evaluating peripheral nerve function in clinical trials and population studies. In this study the correlation between vibratory QST and NCS was determined. Patients (N = 227) with diabetes mellitus participated in this multicenter, single-visit, cross-sectional study. QST of vibration measured with the CASE IV system was compared with a composite score of peroneal motor and tibial motor NCS and with individual attributes of peroneal, tibial, and sural nerves. The correlation between QST and composite score of NCS was 0.234 (Pearson correlation coefficient, P = 0.001). The correlations between QST and individual attributes of NCS ranged from 0.189 to 0.480 (Pearson correlation coefficients, P < 0.001). The low to moderate correlation between QST and NCS suggests that these tests cannot replace each other but are complementary.