RESUMEN
Impaired rate-dependent depression (RDD) of the Hoffman reflex is associated with reduced dorsal spinal cord potassium chloride cotransporter expression and impaired spinal γ-aminobutyric acid type A receptor function, indicative of spinal inhibitory dysfunction. We have investigated the pathogenesis of impaired RDD in diabetic rodents exhibiting features of painful neuropathy and the translational potential of this marker of spinal inhibitory dysfunction in human painful diabetic neuropathy. Impaired RDD and allodynia were present in type 1 and type 2 diabetic rats but not in rats with type 1 diabetes receiving insulin supplementation that did not restore normoglycemia. Impaired RDD in diabetic rats was rapidly normalized by spinal delivery of duloxetine acting via 5-hydroxytryptamine type 2A receptors and temporally coincident with the alleviation of allodynia. Deficits in RDD and corneal nerve density were demonstrated in patients with painful diabetic neuropathy compared with healthy control subjects and patients with painless diabetic neuropathy. Spinal inhibitory dysfunction and peripheral small fiber pathology may contribute to the clinical phenotype in painful diabetic neuropathy. Deficits in RDD may help identify patients with spinally mediated painful diabetic neuropathy who may respond optimally to therapies such as duloxetine.
Asunto(s)
Neuropatías Diabéticas/fisiopatología , Hiperalgesia/fisiopatología , Inhibición Neural/fisiología , Médula Espinal/fisiopatología , Adulto , Anciano , Analgésicos/farmacología , Animales , Western Blotting , Estudios de Casos y Controles , Córnea/inervación , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Neuropatías Diabéticas/etiología , Clorhidrato de Duloxetina/farmacología , Femenino , Humanos , Hiperalgesia/etiología , Hipoglucemiantes/farmacología , Insulina/farmacología , Masculino , Persona de Mediana Edad , Inhibición Neural/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Receptor de Serotonina 5-HT2A , Receptores de GABA-A/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Simportadores/metabolismo , Cotransportadores de K ClRESUMEN
Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor-dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity. M1R-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. Pharmacological blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035, or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetes-induced mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs prevented or reversed indices of peripheral neuropathy, such as depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved for clinical use against other conditions, prompt translation of this therapeutic approach to clinical trials is feasible.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Antagonistas Muscarínicos/farmacología , Receptor Muscarínico M1/antagonistas & inhibidores , Células Receptoras Sensoriales/metabolismo , Animales , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Neuropatías Diabéticas/genética , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/patología , Hiperalgesia/genética , Hiperalgesia/metabolismo , Masculino , Ratones , Ratones Mutantes , Mitocondrias/metabolismo , Mitocondrias/patología , Neuritas/metabolismo , Neuritas/patología , Ratas , Receptor Muscarínico M1/genética , Células Receptoras Sensoriales/patologíaRESUMEN
Neuropathy will afflict over half of the approximately 350 million people worldwide who currently suffer from diabetes and around one-third of diabetic patients with neuropathy will suffer from painful symptoms that may be spontaneous or stimulus evoked. Diabetes can be induced in rats or mice by genetic, dietary, or chemical means, and there are a variety of well-characterized models of diabetic neuropathy that replicate either type 1 or type 2 diabetes. Diabetic rodents display aspects of sensorimotor dysfunction such as stimulus-evoked allodynia and hyperalgesia that are widely used to model painful neuropathy. This allows investigation of pathogenic mechanisms and development of potential therapeutic interventions that may alleviate established pain or prevent onset of pain.
RESUMEN
Anticonvulsants, including gabapentin and carbamazepine, have shown activity against several types of neuropathic pain; however, they have limiting side effects that may minimize their use. In this study the possible synergistic interaction between anticonvulsants and benfotiamine or cyanocobalamin on spinal nerve ligation-induced tactile allodynia was assessed. Oral administration of gabapentin (15-300 mg/kg), carbamazepine (10-300 mg/kg), benfotiamine (30-600 mg/kg) or cyanocobalamin (0.3-6.0 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with gabapentin 300 mg/kg (approximately 70%), carbamazepine 300 mg/kg (approximately 66%), benfotiamine 600 mg/kg (approximately 51%) and cyanocobalamin 6 mg/kg (approximately 59%). At the highest tested doses, gabapentin, but not carbamazepine, benfotiamine or cyanocobalamin, significantly reduced motor coordination. Coadministration of gabapentin or carbamazepine with benfotiamine or cyanocobalamin in a fixed ratio markedly reduced spinal nerve ligation-induced tactile allodynia, showing a synergistic interaction between anticonvulsants and B vitamins. Data indicate that combinations of anticonvulsants with benfotiamine or cyanocobalamin are able to reduce tactile allodynia without affecting motor coordination in rats, and suggest the possible clinical use of these combinations in the treatment of neuropathic pain in humans.
Asunto(s)
Aminas/farmacología , Analgésicos , Anticonvulsivantes/farmacología , Carbamazepina/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Dolor/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Tiamina/análogos & derivados , Vitamina B 12/farmacología , Complejo Vitamínico B/farmacología , Ácido gamma-Aminobutírico/farmacología , Animales , Sinergismo Farmacológico , Femenino , Gabapentina , Ligadura , Dolor/etiología , Dimensión del Dolor/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/patología , Estimulación Física , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Wistar , Nervios Espinales/patología , Tiamina/farmacologíaRESUMEN
The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG)-K(+) channel pathway on melatonin-induced local antinociception was assessed during the second phase of the formalin test. The local peripheral ipsilateral, but not contralateral, administration of melatonin (150-600 microg/paw) produced a dose-related antinociception during both phases of the formalin test in rats. Moreover, local pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, NO synthesis inhibitor, 10-100 microg/paw), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 5-50 microg/paw), (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo [1,2,3-fg:3',2',1'-kl]pyrrolo [3,4-i][1,6] benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor, 50-500 ng/paw), glibenclamide (ATP-sensitive K(+) channel blocker, 5-50 microg/paw), apamin (small-conductance Ca(2+)-activated K(+) channel blocker, 0.1-1 microg/paw) or charybdotoxin (large- and intermediate-conductance Ca(2+)-activated K(+) channel blocker, 0.03-0.3 microg/paw), but not N(G)-D-nitro-arginine methyl ester (D-NAME, inactive isomer of L-NAME, 100 microg/paw) or vehicle, significantly prevented melatonin (300 microg/paw)-induced antinociception. Data suggest that melatonin-induced local peripheral antinociception during the second phase of the test could be due to activation of the NO-cyclic GMP-PKG-ATP-sensitive and Ca(2+)-activated K(+) channels pathway.
Asunto(s)
Proteínas Quinasas Dependientes de GMP Cíclico/fisiología , GMP Cíclico/fisiología , Melatonina/fisiología , Óxido Nítrico/fisiología , Dolor/metabolismo , Canales de Potasio/fisiología , Animales , Femenino , Melatonina/farmacología , Dolor/fisiopatología , Dimensión del Dolor , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/agonistas , Ratas , Ratas WistarRESUMEN
The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10-300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT(2) receptor antagonist, 0.2-2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective delta opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5'-guanidinonaltrindole (a selective kappa opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5'-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75-300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT(2) and delta opioid receptors may play an important role in these effects.
Asunto(s)
Analgésicos , Diabetes Mellitus Experimental/complicaciones , Formaldehído , Melatonina/farmacología , Dimensión del Dolor/efectos de los fármacos , Dolor/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Femenino , Guanidinas/farmacología , Indoles/farmacología , Melatonina/antagonistas & inhibidores , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/etiología , Umbral del Dolor/efectos de los fármacos , Estimulación Física , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Wistar , Receptor de Melatonina MT2/antagonistas & inhibidoresRESUMEN
The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway on gabapentin-induced spinal antiallodynic activity was assessed in spinal nerve injured rats. Intrathecal gabapentin, diazoxide or pinacidil reduced tactile allodynia in a dose-dependent manner. Pretreatment with NG-L-nitro-arginine methyl ester (L-NAME, non-specific inhibitor of NO synthase NOS), 7-nitroindazole (neuronal NO synthase inhibitor), 1H-[1,2,4] -oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor), but not NG-D-nitro-arginine methyl ester (D-NAME) or okadaic acid (protein phosphatase 1 and 2 inhibitor) prevented gabapentin-induced antiallodynia. Pinacidil activity was not blocked by L-NAME, D-NAME, 7-nitroindazole, ODQ, KT-5823 or okadaic acid. Moreover, KT-5823, glibenclamide (ATP-sensitive K+ channel blocker), apamin and charybdotoxin (small- and large-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (voltage-gated K+ channel blocker), L-NAME, 7-nitroindazole, ODQ or okadaic acid, reduced diazoxide-induced antiallodynia. Data suggest that gabapentin-induced spinal antiallodynia could be due to activation of the NO-cyclic GMP-PKG-K+ channel pathway.
Asunto(s)
Aminas/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Dolor/prevención & control , Transducción de Señal/fisiología , Ácido gamma-Aminobutírico/farmacología , Aminas/administración & dosificación , Analgésicos/administración & dosificación , Analgésicos/farmacología , Animales , Apamina/farmacología , Carbazoles/farmacología , Caribdotoxina/farmacología , GMP Cíclico/antagonistas & inhibidores , GMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Ácidos Ciclohexanocarboxílicos/administración & dosificación , Diazóxido/administración & dosificación , Diazóxido/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Femenino , Gabapentina , Gliburida/farmacología , Indazoles/farmacología , Indoles/farmacología , Inyecciones Espinales , NG-Nitroarginina Metil Éster/química , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Ácido Ocadaico/farmacología , Oxadiazoles/farmacología , Dolor/fisiopatología , Pinacidilo/administración & dosificación , Pinacidilo/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/fisiología , Inhibidores de Proteínas Quinasas/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Nervios Espinales/lesiones , Nervios Espinales/fisiopatología , Estereoisomerismo , Factores de Tiempo , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacología , Ácido gamma-Aminobutírico/administración & dosificaciónRESUMEN
The effect of K+ channel inhibitors on the antiallodynic activity induced by spinal gabapentin was assessed in rats. Ligation of L5 and L6 spinal nerves made the rats allodynic, whereas that intrathecal administration of gabapentin (25-200 microg) reduced tactile allodynia in a dose-dependent manner. Spinal pretreatment with glibenclamide (12.5-50 microg, ATP-sensitive K+ channel inhibitor), charybdotoxin (0.01-1 ng) or apamin (0.1-3 ng, large-and small-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (0.01-10 ng, voltage-dependent K+ channel inhibitor), significantly prevented gabapentin-induced antiallodynia. Pinacidil (1-30 microg, K+ channel opener) significantly reduced nerve ligation-induced allodynia. Intrathecal glibenclamide (50 microg), charybdotoxin (1 ng) and apamin (3 ng), but not margatoxin (10 ng), significantly reduced pinacidil-induced antiallodynia. K+ channel inhibitors alone did not modify allodynia produced by spinal nerve ligation. Results suggest that gabapentin and pinacidil may activate Ca2+-activated and ATP-sensitive K+ channels in order to produce part of its spinal antiallodynic effect in the Chung model.