RESUMEN
Neuropathic pain is a severe problem that is difficult to treat clinically. Reducing abnormal remodeling of dendritic spines/synapses and increasing the anti-inflammatory effects in the spinal cord dorsal horn are potential methods to treat this disease. Previous studies have reported that electroacupuncture (EA) could increase the pain threshold after peripheral nerve injury. However, the underlying mechanism is unclear. P2X7 receptors (P2X7R) mediate the activation of microglia and participate in the occurrence and development of neuropathic pain. We hypothesized that the effects of EA on relieving pain may be related to the downregulation of the P2X7R. Spinal nerve ligation (SNL) rats were used as a model in this experiment, and 2'(3')-O-(4-benzoyl)benzoyl ATP (BzATP) was used as a P2X7R agonist. We found that EA treatment decreased dendritic spine density, inhibited synaptic reconstruction and reduced inflammatory response, which is consistent with the decrease in P2X7R expression as well as the improved neurobehavioral performance. In contrast to the beneficial effects of EA, BzATP enhanced abnormal remodeling of dendritic spines/synapses and inflammation. Furthermore, the EA-mediated positive effects were reversed by BzATP, which is consistent with the increased P2X7R expression. These findings indicated that EA improves neuropathic pain by reducing abnormal dendritic spine/synaptic reconstruction and inflammation via suppressing P2X7R expression.
Asunto(s)
Electroacupuntura , Neuralgia/metabolismo , Neuralgia/terapia , Receptores Purinérgicos P2X7/metabolismo , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Animales , Espinas Dendríticas/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Ligadura , Masculino , Modelos Biológicos , Proteínas del Tejido Nervioso/metabolismo , Neuralgia/fisiopatología , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/patología , Umbral del Dolor/efectos de los fármacos , Ratas Sprague-Dawley , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/patología , Nervios Espinales/efectos de los fármacos , Nervios Espinales/patología , Nervios Espinales/fisiopatologíaAsunto(s)
Anestesia Local/métodos , Antiinflamatorios/administración & dosificación , Cefalalgia Histamínica/tratamiento farmacológico , Metilprednisolona/administración & dosificación , Complicaciones del Embarazo/tratamiento farmacológico , Nervios Espinales/efectos de los fármacos , Adulto , Cefalalgia Histamínica/diagnóstico , Femenino , Humanos , Recién Nacido , Embarazo , Complicaciones del Embarazo/diagnóstico , Nervios Espinales/patologíaRESUMEN
AIMS: To determine the role of opioid receptors in the inhibition of bladder overactivity by sacral neuromodulation (SNM) in pigs, and explore the possible mechanism of SNM. METHODS: Both implant-driven stimulators of the S3 spinal nerve were implanted in seven pigs. Naloxone and tramadol were administered. Multiple cystometrograms were performed to determine the effects of SNM and opioid receptors on the micturition reflex by infusing normal saline (NS) or acetic acid (AA). RESULTS: AA-induced bladder overactivity significantly reduced the bladder capacity (BC) to 29.9 ± 3.9% of the NS control level (413.1 ± 55.4 mL) (P < 0.01). SNM significantly increased the BC to 39.4 ± 5.5% of the NS control level (P < 0.03). In the absence of SNM, the cumulative dose of naloxone (0.02 and 0.2 mg/kg intravenously) did not significantly change the BC (25.1 ± 3.1% and 20.2 ± 3.1% of the NS control level, respectively) (P > 0.05). In the presence of SNM, both doses of naloxone significantly reduced the BC to 27.2 ± 3.0% and 25.1 ± 2.9% of the NS control level (P < 0.05), respectively. In the absence of SNM, tramadol did not significantly change the BC (31.5 ± 3.9% of the NS control level) (P > 0.05). In the presence of SNM, tramadol significantly increased the BC to 49.1 ± 6.1% of the NS control level (P < 0.01). CONCLUSIONS: Opioid receptors play a role in inhibition of bladder overactivity during SNM. Combining SNM with tramadol could be a novel treatment modality for overactive bladder.
Asunto(s)
Naloxona/farmacología , Nervios Espinales/efectos de los fármacos , Tramadol/farmacología , Estimulación Eléctrica Transcutánea del Nervio , Vejiga Urinaria Hiperactiva/terapia , Micción/fisiología , Ácido Acético , Animales , Femenino , Masculino , Naloxona/uso terapéutico , Reflejo/efectos de los fármacos , Sacro , Porcinos , Vejiga Urinaria Hiperactiva/inducido químicamente , Vejiga Urinaria Hiperactiva/fisiopatología , Micción/efectos de los fármacosRESUMEN
BACKGROUND: Following neuropathy α2-adrenoceptor-mediated diffuse noxious inhibitory controls (DNIC), whereby a noxious conditioning stimulus inhibits the activity of spinal wide dynamic range (WDR) neurons, are abolished, and spinal 5-HT7 receptor densities are increased. Here, we manipulate spinal 5-HT content in spinal nerve ligated (SNL) animals and investigate which 5-HT receptor mediated actions predominate. METHODS: Using in vivo electrophysiology we recorded WDR neuronal responses to von frey filaments applied to the hind paw before, and concurrent to, a noxious ear pinch (the conditioning stimulus) in isoflurane-anaesthetised rats. The expression of DNIC was quantified as a reduction in WDR neuronal firing in the presence of conditioning stimulus and was investigated in SNL rats following spinal application of (1) selective serotonin reuptake inhibitors (SSRIs) citalopram or fluoxetine, or dual application of (2) SSRI plus 5-HT7 receptor antagonist SB269970, or (3) SSRI plus α2 adrenoceptor antagonist atipamezole. RESULTS: DNIC were revealed in SNL animals following spinal application of SSRI, but this effect was abolished upon joint application of SSRI plus SB269970 or atipamezole. CONCLUSIONS: We propose that in SNL animals the inhibitory actions (quantified as the presence of DNIC) of excess spinal 5-HT (presumed present following application of SSRI) were mediated via 5-HT7 receptors. The anti-nociception depends upon an underlying tonic noradrenergic inhibitory tone via the α2-adrenoceptor. SIGNIFICANCE: Following neuropathy enhanced spinal serotonin availability switches the predominant spinal 5-HT receptor-mediated actions but also alters noradrenergic signalling. We highlight the therapeutic complexity of SSRIs and monoamine modulators for the treatment of neuropathic pain.
Asunto(s)
Control Inhibidor Nocivo Difuso/fisiología , Neuralgia/fisiopatología , Serotonina/fisiología , Animales , Control Inhibidor Nocivo Difuso/efectos de los fármacos , Fluoxetina/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fenoles/farmacología , Prilocaína/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatología , Nervios Espinales/efectos de los fármacos , Nervios Espinales/fisiopatología , Sulfonamidas/farmacologíaRESUMEN
OBJECTIVE: To investigate the effects of maca extract on the ultrastructures of mitochondria in the spinal nerve cell and exercise endurance. METHODS: The Wistar rats were randomly divided into 5 groups, including the control group (no swimming), the swimming group (free swimming), and 3 treatment groups treated with the maca extract at the doses of 4.0, 5.3 and 8.0 g/kg body weight. The animals in swimming and treatment groups were then for free swimming in the circulating water flow daily for 15 days. On the 16th day after swimming endurance, the spinal and muscular tissues were collected from all groups. The mitochondrial ultrastructures of the neurons of the spinal cells were observed with the projection electron microscope, and the levels of the glycogen, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and Ca2+ in muscle tissues were determined by the RIA method. RESULTS: When rats were treated with maca extract (at 4.0, 5.3, 8.0 g/kg body weight), the total swimming time and the swimming duration before sinking were increased by 19.83%, 60.28%, 77.55%, and 55.34%, 73.91%, 94.47%, respectively, compared with the simple swimming group(P<0.01), while the sinking times were decreased by 34.35%, 51.18% and 57.96%, compared with those of the swimming group. Also, the levels of SOD, GSH-Px, and muscle glycogen in three treatment groups were enhanced by 5.12%, 22.74%, 52.53%, 44.22%, 77.79%, 98.45%(P<0.01), and 35.08%, 47.83%,81.88% (P<0.01)respectively over the swimming rats without treatment, but the MDA content and the Ca2+ levels were reduced by 20.10%, 31.49% 38.72%, and 6.42%, 17.58%, 26.35%,compared with the simple swimming group(P<0.01). In addition, compared to the swimming group, the mitochondrial densities of volume (VD), surface (SD) and numbers (ND) of spinal nerve cells in rats treated with maca extract (4.0, 5.3, 8.0 g/kg body weight) were reduced by 7.79%, 18.18%, 31.17%, 16.95%, 27.34%, 43.31% and 13.51%, 23.19%, 43.15%, respectively. CONCLUSIONS: Our results demonstrated the protective effects of maca extract on the mitochondria of spinal cell and suggested that maca extract could improve the muscle antioxidant activity by increasing the levels of SOD, GSH-Px, and muscle glycogen.
Asunto(s)
Lepidium/química , Mitocondrias/ultraestructura , Condicionamiento Físico Animal , Resistencia Física/efectos de los fármacos , Extractos Vegetales/farmacología , Nervios Espinales/ultraestructura , Animales , Antioxidantes/análisis , Glutatión Peroxidasa/análisis , Glucógeno/análisis , Malondialdehído/análisis , Mitocondrias/efectos de los fármacos , Ratas , Ratas Wistar , Nervios Espinales/efectos de los fármacos , Superóxido Dismutasa/análisisRESUMEN
Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex; however, under neuropathic conditions, it is unclear how hyperexcitability of spinal neurons converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurons in anesthetized spinal nerve-ligated (SNL), sham-operated, and naive rats. In neuropathic rats, WDR neurons had elevated evoked responses to low- and high-intensity punctate mechanical stimuli, dynamic brushing, and innocuous and noxious cooling, but less so to heat stimulation, of the receptive field. NS neurons in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling, and noxious heat. Additionally, WDR, but not NS, neurons in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR-to-NS neurons was comparable between SNL and naive/sham groups, suggesting relatively few NS neurons gain sensitivity to low-intensity stimuli leading to a "WDR phenotype." After neuropathy was induced, the proportion of cold-sensitive WDR and NS neurons increased, supporting the suggestion that changes in frequency-dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold-evoked or elevated spontaneous activity.
Asunto(s)
Analgésicos/farmacología , Neuralgia/fisiopatología , Neuronas/fisiología , Pregabalina/farmacología , Tálamo/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Ligadura , Masculino , Microelectrodos , Neuralgia/tratamiento farmacológico , Neuronas/efectos de los fármacos , Estimulación Física , Ratas Sprague-Dawley , Nervios Espinales/efectos de los fármacos , Nervios Espinales/fisiopatología , Tálamo/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate whether analgesic effect of electroacupuncture (EA) is affected by p38 mitogen-activated protein kinase (p38 MAPK) on microglia. METHODS: There were two experiments. The experiment 1: 40 male Sprague-Dawley (SD) rats were randomly divided into the normal, surgery, EA and sham EA groups, and the L5 spinal nerve ligation (SNL) on the right side was used to establish neuropathic pain model. EA was applied to bilateral Zusanli (ST36) and Kunlun (BL60) at 24, 48 and 72 h after SNL for 30 min, once per day. The paw withdrawal thresholds (PWTs) were measured before surgery (as base) and at 24, 25, 49 and 73 h after surgery. Phospho-p38 MAPK (p-p38 MAPK), oxycocin-42 (OX-42, marker of microglia), and glial fibrillary acidic protein (GFAP, marker of astrocyte) in bilateral spinal cord dorsal horn (SCDH) were detected by immunofluorescence, respectively. The experiment 2: 40 male SD rats were cannulated for SNL-induced neuropathic pain, and then were randomly divided into the dimethyl sulfoxide (DMSO), EA plus DMSO, 4-(4-fluorophenyl)-2-(4-methylsulfonylpheny)-5-(4-pyridyl)-1H-imidazole (SB203580) and EA plus SB203580 groups. SB203580 (30 nmol/L) was administered 5 min prior to EA treatment. The PWTs and OX-42 in bilateral SCDH were measured as mentioned above. RESULTS: SNL-induced neuropathic pain reduced PWTs and increased the expression of p-p38 MAPK and OX-42 in bilateral lumbar SCDH of rats (P<0.01). Spinal p-p38 MAPK was only co-localized with OX-42 in our study. EA treatment significantly alleviated SNL-mediated mechanical hyperalgesia, and suppressed the expression of p-p38 MAPK and OX-42 in lumbar SCDH (P<0.05 or P<0.01). Intrathecal injection of low dose SB203580 had no influence on PWTs (P>0.05), but significantly inhibited the expression of OX-42 positive cells in bilateral SCDH (P<0.01 or P<0.05). EA plus SB203580 synergistically increased PWTs, and reduced the expression of bilateral spinal OX-42 (P<0.01 or P<0.05). CONCLUSIONS: The central mechanism of EA-induced anti-hyperalgesia may be partially associated with the reduced expression of p-p38 MAPK, and subsequently reducing the activation of OX-42 in neuropathic pain. Therefore, EA may be a new complementary and alternative therapy for neuropathic pain.
Asunto(s)
Electroacupuntura , Microglía/enzimología , Microglía/patología , Nervios Espinales/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Biomarcadores/metabolismo , Antígeno CD11b/metabolismo , Técnica del Anticuerpo Fluorescente , Hiperalgesia/patología , Hiperalgesia/terapia , Imidazoles/farmacología , Ligadura , Masculino , Microglía/efectos de los fármacos , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Fosforilación/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/enzimología , Células del Asta Posterior/patología , Piridinas/farmacología , Ratas Sprague-Dawley , Nervios Espinales/efectos de los fármacosRESUMEN
Scolopendra extracts were used for pharmacopuncture at the Kidney 1 acupoint to investigate the role of Scolopendra pharmacopuncture (SPP) in both the development and maintenance of neuropathic pain induced by L5 spinal nerve ligation in rats and the contribution of spinal glial cells. A single treatment and five once-daily treatments with SPP were given to evaluate its effects on the development and maintenance stages of neuropathic pain, respectively, which was followed by behavioral tests. Immunohistochemistry and Western blotting tests were also carried out. A single treatment of SPP delayed spinal nerve ligation-induced mechanical allodynia and thermal hyperalgesia and induced a profound decrease in the expression of ionized calcium binding adaptor protein in the lumbar spinal cord. Repeated SPP treatments reliably suppressed mechanical allodynia and thermal hyperalgesia at later time points, and these results correlated mainly with decreases in glial fibrillary acidic protein. Intriguingly, ionized calcium binding adaptor protein expression was also reduced after repeated SPP. These results illustrate that neuropathic pain in the development and maintenance stages is alleviated by SPP treatment, which may be ascribed principally to deactivations of microglia and astroglia, respectively. Additionally, microglial inactivation seems to be partially involved in preventing neuropathic pain in the maintenance stage.
Asunto(s)
Analgesia por Acupuntura/métodos , Antiinflamatorios/farmacología , Medicamentos Herbarios Chinos/farmacología , Neuralgia/terapia , Neuroglía/efectos de los fármacos , Nervios Espinales/efectos de los fármacos , Animales , Antiinflamatorios/uso terapéutico , Alcaloides Diterpénicos , Medicamentos Herbarios Chinos/uso terapéutico , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Diabetic erectile dysfunction is associated with penile dorsal nerve bundle neuropathy in the corpus cavernosum and the mechanism is not well understood. We investigated the neuropathy changes in the corpus cavernosum of rats with streptozotocin-induced diabetes and the effects of Icariside II (ICA II) on improving neuropathy. Thirty-six 8-week-old Sprague-Dawley rats were randomly distributed into normal control group, diabetic group and ICA-II treated group. Diabetes was induced by a one-time intraperitoneal injection of streptozotocin (60 mg/kg). Three days later, the diabetic rats were randomly divided into 2 groups including a saline treated placebo group and an ICA II-treated group (5 mg/kg/day, by intragastric administration daily). Twelve weeks later, erectile function was measured by cavernous nerve electrostimulation with real time intracorporal pressure assessment. The penis was harvested for the histological examination (immunofluorescence and immunohistochemical staining) and transmission electron microscopy detecting. Diabetic animals exhibited a decreased density of dorsal nerve bundle in penis. The neurofilament of the dorsal nerve bundle was fragmented in the diabetic rats. There was a decreased expression of nNOS and NGF in the diabetic group. The ICA II group had higher density of dorsal nerve bundle, higher expression of NGF and nNOS in the penis. The pathological change of major pelvic nerve ganglion (including the microstructure by transmission electron microscope and the neurite outgrowth length of major pelvic nerve ganglion tissue cultured in vitro) was greatly attenuated in the ICA II-treated group (p < 0.01). ICA II treatment attenuates the diabetes-related impairment of corpus cavernosum and major pelvic ganglion neuropathy in rats with Streptozotocin-Induced Diabetes.
Asunto(s)
Neuropatías Diabéticas/tratamiento farmacológico , Flavonoides/uso terapéutico , Pene/efectos de los fármacos , Nervios Espinales/efectos de los fármacos , Animales , Flavonoides/farmacología , Masculino , Factor de Crecimiento Nervioso/genética , Factor de Crecimiento Nervioso/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Pelvis/inervación , Pene/inervación , Pene/metabolismo , Ratas , Ratas Sprague-Dawley , Nervios Espinales/metabolismo , Nervios Espinales/ultraestructuraRESUMEN
BACKGROUND: Diluted bee venom (BV) is known to have anti-nociceptive and anti-inflammatory effects. We therefore assessed whether perineural bee venom pretreatment could attenuate the development of neuropathic pain in the spinal nerve ligation injured animal model. METHODS: Neuropathic pain was surgically induced in 30 male Sprague Dawley rats by ligation of the L5 and L6 spinal nerves, with 10 rats each treated with saline and 0.05 and 0.1 mg BV. Behavioral testing for mechanical, cold, and thermal allodynia was conducted on postoperative days 3 to 29. Three rats in each group and 9 sham operated rats were sacrificed on day 9, and the expression of transient receptor potential vanilloid type 1 (TRPV1), ankyrin type 1 (TRPA1), and melastatin type 8 (TRPM8) receptors in the ipsilateral L5 dorsal root ganglion was analyzed. RESULTS: The perineural administration of BV to the spinal nerves attenuated the development of mechanical, thermal, and cold allodynia, and the BV pretreatment reduced the expression of TRPV1, TRPA1, TRPM8 and c - Fos in the ipsilateral dorsal root ganglion. CONCLUSION: The current study demonstrates that the perineural pretreatment with diluted bee venom before the induction of spinal nerve ligation significantly suppresses the development of neuropathic pain. Furthermore, this bee venom induced suppression was strongly related with the involvement of transient receptor potential family members.
Asunto(s)
Venenos de Abeja/uso terapéutico , Ganglios Espinales/efectos de los fármacos , Hiperalgesia/prevención & control , Neuralgia/prevención & control , Nervios Espinales/efectos de los fármacos , Animales , Venenos de Abeja/administración & dosificación , Venenos de Abeja/farmacología , Modelos Animales de Enfermedad , Ganglios Espinales/metabolismo , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Ligadura , Región Lumbosacra , Masculino , Neuralgia/etiología , Neuralgia/metabolismo , Ratas , Ratas Sprague-Dawley , Nervios Espinales/lesiones , Nervios Espinales/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismoRESUMEN
CONTEXT: Guggulipid is a neutral fraction of ethyl acetate extract of gum resin of the tree Commiphora mukul Engl. (Burseraceae) and used in Ayurvedic medicine for treatment of neurological disorders. OBJECTIVES: The present study was undertaken to assess the antiallodynic and antihyperalgesic activities of guggulipid in rats. MATERIALS AND METHODS: The screening study included the CCI and L5-L6 SNL models of neuropathic pain. Guggulipid (100 and 50 mg/kg) or saline was administered intraperitoneally in a blinded, randomized manner from postoperative day (POD) 7 to 13. Paw withdrawal duration (PWD) to spontaneous pain, chemical allodynia and mechanical hyperalgesia and paw withdrawal latency (PWL) to mechanical allodynia and thermal hyperalgesia were tested before surgery, before and after guggulipid or saline administration (from POD7 to 13) and after the withdrawal of treatment (from POD14 to 20). RESULTS: The activity profiles of the different doses of guggulipid were found to vary with time. In CCI rats, guggulipid (100 and 50 mg/kg) significantly (p < 0.05) reduced the spontaneous pain, mechanical allodynia and mechanical and thermal hyperalgesia responses and the LD50 of guggulipid was 1600 mg/kg. In SNL rats, both doses of guggulipid were found to be ineffective in reversing the spontaneous pain but showing antiallodynic and antihyperalgesic activity. DISCUSSION AND CONCLUSION: The results demonstrated that guggulipid produce antinociception in the peripheral nerve injury (CCI and SNL) models of neuropathic pain. The underlying mechanisms are expected to be modulating microglial activation occurring due to peripheral nerve injury.
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Commiphora/química , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Gomas de Plantas/uso terapéutico , Nervio Ciático/efectos de los fármacos , Nervios Espinales/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hiperalgesia/etiología , Hiperalgesia/patología , Masculino , Medicina Ayurvédica , Neuralgia/complicaciones , Neuralgia/patología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Gomas de Plantas/administración & dosificación , Gomas de Plantas/aislamiento & purificación , Gomas de Plantas/toxicidad , Ratas , Ratas Sprague-Dawley , Nervio Ciático/patología , Nervios Espinales/patologíaRESUMEN
Acetaminophen (ACT) facilitates the inhibition of voltage-gated calcium and sodium currents, which may effect cortico-spinal excitability. Twelve subjects ingested acetaminophen or a placebo and underwent transcranial magnetic stimulation to assess the motor evoked potential (MEP), and cortical silent period (CSP). ACT significantly increased MEP response (P > 0.05) but had no effect on CSP (P > 0.05). This indicates that ACT increases MEP and should be controlled for in studies where these measures are of interest.
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Acetaminofén/farmacología , Antiinflamatorios no Esteroideos/farmacocinética , Potenciales Evocados Motores/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Nervios Espinales/efectos de los fármacos , Acetaminofén/administración & dosificación , Análisis de Varianza , Antiinflamatorios no Esteroideos/administración & dosificación , Mapeo Encefálico , Método Doble Ciego , Electromiografía , Femenino , Humanos , Contracción Isométrica/efectos de los fármacos , Masculino , Corteza Motora/fisiología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inervación , Desempeño Psicomotor/efectos de los fármacos , Umbral Sensorial/efectos de los fármacos , Nervios Espinales/fisiología , Estimulación Magnética TranscranealRESUMEN
The compound (±)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one [(±)-δ-lactone] was isolated from the plant Vitex cymosa Bertero, and determined to be the active principle. The present study aimed to evaluate the antinociceptive effect of (±)-δ-lactone and to elucidate its mechanism of action. Mice were subjected to in-vivo models of acute pain (acetic acid-induced abdominal writhing, formalin and hot-plate tests) and the open-field test. (±)-δ-Lactone, administered orally (6-900 µmol/kg), exerted a dose-dependent antinociceptive effect in the acetic acid-induced abdominal writhing, formalin and hot-plate tests. (±)-δ-Lactone administered by the intrathecal (i.t.) and subplantar (s.p.) routes (10-600 nmol) exerted concentration-dependent antinociceptive effects in the formalin test, showing its spinal and peripheral activity, respectively. In the hot-plate test, (±)-δ-lactone was also active when administered i.t., confirming its spinal effect. The previous intraperitoneal (i.p.) application of naloxone, yohimbine, mecamylamine or glibenclamide did not alter the effect produced by the i.t. administration of (±)-δ-lactone, whereas the previous application of atropine and L-arginine significantly reduced its effects in the formalin and hot-plate tests. The previous i.p. application of L-NAME enhanced the antinociceptive effect of the i.t. administration of (±)-δ-lactone in the formalin and hot-plate tests. The previous i.p. application of L-NAME and L-arginine increased and decreased, respectively, the activity of (±)-δ-lactone administered by s.p. administration. These results indicate that (±)-δ-lactone has significant spinal and peripheral antinociceptive activity, and that its effects are at least partially mediated by a reduced nitric oxide production/release, most likely through mechanisms involving the cholinergic system.
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Dolor Agudo/prevención & control , Analgésicos no Narcóticos/uso terapéutico , Neuronas Colinérgicas/efectos de los fármacos , Lactonas/uso terapéutico , Óxido Nítrico/antagonistas & inhibidores , Nervios Periféricos/efectos de los fármacos , Nervios Espinales/efectos de los fármacos , Dolor Agudo/metabolismo , Administración Oral , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/efectos adversos , Analgésicos no Narcóticos/antagonistas & inhibidores , Animales , Conducta Animal/efectos de los fármacos , Brasil , Neuronas Colinérgicas/metabolismo , Relación Dosis-Respuesta a Droga , Etnofarmacología , Conducta Exploratoria/efectos de los fármacos , Inyecciones Espinales , Inyecciones Subcutáneas , Lactonas/administración & dosificación , Lactonas/efectos adversos , Lactonas/antagonistas & inhibidores , Masculino , Ratones , Óxido Nítrico/metabolismo , Dimensión del Dolor/efectos de los fármacos , Nervios Periféricos/metabolismo , Nervios Espinales/metabolismo , Vitex/químicaRESUMEN
OBJECTIVES: Quinidine, a class I anti-arrhythmic agent, is a sodium channel blocker that is more potent than lidocaine and mexiletine. This study tested pre-emptive intrathecal quinidine to attenuate neuropathic pain induced by lumbar spinal nerve ligation (SNL). METHODS: Ninety-six adult male Sprague-Dawley rats were grouped equally (n=24 per group) as follows: group S (sham), removal of transverse process only; group L, SNL; group Q35, SNL pretreated with intrathecal quinidine 35 mM (50 µl); group Q70, SNL pretreated with intrathecal quinidine 70 mM (50 µl). Neuropathic pain was measured by thermal hyperalgesia and mechanical allodynia. Other measurements included dys-regulation of sodium channel Nav1.3 in dorsal root ganglion (DRG) and spinal microglia activation in spinal dorsal horn. KEY FINDINGS: Spinal nerve ligation induced abnormal mechanical allodynia and thermal hyperalgesia, up-regulated Nav1.3 in DRG, and activated microglia in spinal cord. Group Q70 showed attenuated thermal hyperalgesia (P<0.001) and mechanical allodynia (P<0.05) on postoperative day 5 (POD5) but not on POD7, reversed up-regulated expression of Nav1.3 on POD3 and POD7 in DRG and significantly attenuated microglia activation on POD7 (P=0.032) in spinal cord. CONCLUSIONS: Pretreatment with intrathecal quinidine 70 mM before SNL attenuates nerve ligation-induced neuropathic pain. The duration of the effect is 5 days.
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Analgésicos/uso terapéutico , Cinchona/química , Neuralgia/tratamiento farmacológico , Fitoterapia , Quinidina/uso terapéutico , Bloqueadores de los Canales de Sodio/uso terapéutico , Nervios Espinales/efectos de los fármacos , Analgésicos/farmacología , Animales , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/prevención & control , Masculino , Microglía/efectos de los fármacos , Canal de Sodio Activado por Voltaje NAV1.3 , Proteínas del Tejido Nervioso/metabolismo , Neuralgia/etiología , Neuralgia/metabolismo , Dimensión del Dolor , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Quinidina/farmacología , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Nervios Espinales/metabolismo , Nervios Espinales/patología , Regulación hacia ArribaRESUMEN
Hemokinin-1 is a novel mammalian tachykinin cloned from mouse bone marrow. At present, pharmacological profile and physiological role of hemokinin-1 are still unclear. In the present study, we found that intrathecal (i.t.) administration of hemokinin-1 (0.00625-1.6 nmol) induced nociceptive responses consisting of scratching, biting and licking, which resemble substance P-induced behavioral responses in mice. The behaviors evoked by low-dose of hemokinin-1 (0.0125 nmol) were dose-dependently inhibited by i.t. co-administration of CP-99,994, a non-peptidic tachykinin NK(1) receptor antagonist, whereas high-dose of hemokinin-1 (0.1 nmol)-induced behaviors were not affected. Moreover, sendide, a peptidic tachykinin NK(1) receptor antagonist, failed to reduce the behavioral responses of both low- and high-dose of hemokinin-1. In contrast, substance P-induced behaviors were completely suppressed by both CP-99,994 and sendide. These results suggest that hemokinin-1 plays an important role in pain transmission at spinal cord. Moreover, the mechanism of hemokinin-1-induced nociceptive behaviors may be dose-dependent, and distinct from substance P-induced nociceptive behaviors.
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Conducta Animal/efectos de los fármacos , Vértebras Lumbares/inervación , Dolor/fisiopatología , Nervios Espinales/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Taquicininas/administración & dosificación , Taquicininas/fisiología , Analgésicos/administración & dosificación , Analgésicos/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Inyecciones Espinales , Masculino , Ratones , Antagonistas del Receptor de Neuroquinina-1 , Neurotransmisores/administración & dosificación , Neurotransmisores/uso terapéutico , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dimensión del Dolor , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/uso terapéutico , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Ácido Pirrolidona Carboxílico/administración & dosificación , Ácido Pirrolidona Carboxílico/análogos & derivados , Ácido Pirrolidona Carboxílico/uso terapéutico , Receptores de Neuroquinina-1/metabolismo , Nervios Espinales/efectos de los fármacos , Sustancia P/administración & dosificación , Sustancia P/antagonistas & inhibidores , Sustancia P/fisiología , Sustancia P/uso terapéutico , Taquicininas/antagonistas & inhibidores , Factores de TiempoRESUMEN
This study was performed to determine whether spinal cholinergic systems mediate the relieving effects of electroacupuncture (EA) on cold and warm allodynia in a rat model of neuropathic pain. For neuropathic surgery, the right superior caudal trunk was resected at the level between the S1 and S2 spinal nerves innervating the tail. Two weeks after the injury, the intrathecal (i.t.) catheter was implanted. Five days after the catheterization, the rats were injected with atropine (non-selective muscarinic antagonist, 30 microg), mecamylamine (non-selective nicotinic antagonist, 50 microg), pirenzepine (M(1) muscarinic antagonist, 10 microg), methoctramine (M(2) antagonist, 10 microg) or 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (M(3) antagonist, 10 microg). Ten minutes after the injection, EA was applied to the ST36 acupoint for 30 min. The cold and warm allodynia were assessed by the tail immersion test [i.e., immersing the tail in cold (4 degrees C) or warm (40 degrees C) water and measuring the latency of an abrupt tail movement] before and after the treatments. The i.t. atropine, but not mecamylamine, blocked the relieving effects of EA on cold and warm allodynia. Furthermore, i.t. pirenzepine attenuated the antiallodynic effects of EA, whereas methoctramine and 4-DAMP did not. These results suggest that spinal muscarinic receptors, especially M(1) subtype, mediate the EA-induced antiallodynia in neuropathic rats.
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Fibras Colinérgicas/fisiología , Electroacupuntura , Neuralgia/fisiopatología , Neuralgia/terapia , Nervios Espinales/fisiopatología , Animales , Atropina/farmacología , Colinérgicos/farmacología , Fibras Colinérgicas/efectos de los fármacos , Frío , Diaminas/farmacología , Modelos Animales de Enfermedad , Calor , Hiperestesia/fisiopatología , Hiperestesia/terapia , Masculino , Mecamilamina/farmacología , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Piperidinas/farmacología , Pirenzepina/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M1/efectos de los fármacos , Receptor Muscarínico M1/fisiología , Nervios Espinales/efectos de los fármacosRESUMEN
BACKGROUND: Based on the criteria established by the International Association for the Study of Pain, the prevalence of persistent neck pain, secondary to involvement of cervical facet or zygapophysial joints has been described in controlled studies as varying from 54% to 67%. Intraarticular injections, medial branch nerve blocks and neurolysis of medial branch nerves have been described in managing chronic neck pain of facet joint origin. OBJECTIVES: To determine the clinical effectiveness of therapeutic cervical medial branch blocks in managing chronic neck pain of facet joint origin and to evaluate the effectiveness of the addition of Sarapin and steroids to local anesthetics. DESIGN: A double-blind, randomized, controlled trial. SETTING: An interventional pain management setting in the United States. METHODS: In this preliminary analysis, data from a total of 60 patients were included, with 15 patients in each of the 4 groups. Thirty patients were in a non-steroid group (combined Group I and II); and 30 patients were in a steroid group (combined Group III and IV). All of the patients met the diagnostic criteria of cervical facet joint pain by means of comparative, controlled diagnostic blocks. Four types of interventions were included. Group I served as control, receiving medial branch blocks using bupivacaine. Group II consisted of cervical medial branch blocks with bupivacaine and Sarapin. Group III consisted of cervical medial branch blocks with bupivacaine and betamethasone. Group IV consisted of cervical medial branch blocks with bupivacaine, Sarapin and betamethasone. OUTCOME MEASURES: Numeric pain scores, Neck Pain Disability Index, opioid intake, and work status were evaluated at baseline, 3 months, 6 months and 12 months. RESULTS: Significant pain relief (> or =50%), and functional status improvement was observed at 3 months, 6 months and 12 months. The average number of treatments for 1 year was 3.8 +/- 0.7 in the non-steroid group and 3.4 +/- 1.0 in the steroid group with no significant difference among the groups. Duration of average pain relief with each procedure was 13.4 +/- 3.5 weeks in the nonsteroid group, and it was 15.9 +/- 8.0 weeks in the steroid group with no significant difference among the groups. CONCLUSION: Therapeutic cervical medial branch nerve blocks, with or without Sarapin or steroids, may provide effective management for chronic neck pain of facet joint origin.
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Analgesia/métodos , Anestésicos Locales/administración & dosificación , Dolor de Cuello/tratamiento farmacológico , Bloqueo Nervioso/métodos , Nervios Espinales/efectos de los fármacos , Articulación Cigapofisaria/fisiopatología , Adulto , Anciano , Analgesia/tendencias , Analgésicos Opioides/uso terapéutico , Antiinflamatorios/administración & dosificación , Artralgia/tratamiento farmacológico , Artralgia/etiología , Artralgia/fisiopatología , Betametasona/administración & dosificación , Bupivacaína/administración & dosificación , Evaluación de la Discapacidad , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor de Cuello/etiología , Dolor de Cuello/fisiopatología , Bloqueo Nervioso/tendencias , Dolor Intratable/tratamiento farmacológico , Dolor Intratable/etiología , Dolor Intratable/fisiopatología , Extractos Vegetales/administración & dosificación , Nervios Espinales/fisiopatología , Osteofitosis Vertebral/tratamiento farmacológico , Osteofitosis Vertebral/fisiopatología , Resultado del Tratamiento , Articulación Cigapofisaria/inervaciónRESUMEN
This paper describes the patterns of pain induced by injecting hypertonic saline into the lumbar multifidus muscle opposite the L5 spinous process in 15 healthy adult volunteers. All subjects experienced local pain while referred pain was reported by 13 subjects in one of two regions of the thigh; anterior (n=5) or posterior (n=8). These results confirm that the multifidus muscle may be a source of local and referred pain. Comparison of these maps with pain maps following stimulation of the L4 medial dorsal rami and L4-5 interspinous ligaments shows that pain arising from the band of multifidus innervated by the L4 dorsal ramus has a segmental distribution. In addition patterns of pain arising from multifidus clearly overlap those reported for other lumbar structures. These findings highlight the difficulty of using pain distribution to accurately identify specific lumbar structures as the source of pain.
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Músculo Esquelético/fisiología , Dolor/diagnóstico , Dolor/fisiopatología , Nervios Espinales/fisiología , Adulto , Diagnóstico Diferencial , Método Doble Ciego , Femenino , Humanos , Región Lumbosacra , Masculino , Persona de Mediana Edad , Músculo Esquelético/efectos de los fármacos , Manipulaciones Musculoesqueléticas/organización & administración , Dolor/etiología , Dimensión del Dolor , Presión , Valores de Referencia , Solución Salina Hipertónica/administración & dosificación , Nervios Espinales/efectos de los fármacosRESUMEN
Cluster headache is marked by its circadian rhythmicity and the hypothalamus appears to have a significant influence over cluster pathogenesis. However, as not all cluster patients present in the same manner and not all respond to the same combination of medications, there is likely a nonhypothalamic form of cluster headache. A patient is presented who began to develop cluster headaches after receiving bilateral greater occipital nerve (GON) blockade. His headaches fit the IHS criteria for cluster headache but had some irregularities including frequent side shifting of pain, irregular duration and time of onset and the ability of the patient to sit completely still during a headache without any sense of agitation. This article will suggest that some forms of cluster headache are not primarily hypothalamic influenced and that the GON may play a significant role in cluster pathogenesis in some individuals.
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Cefalalgia Histamínica/inducido químicamente , Bloqueo Nervioso/efectos adversos , Neuralgia/complicaciones , Neuralgia/tratamiento farmacológico , Nervios Espinales/efectos de los fármacos , Nervios Espinales/fisiopatología , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiopatología , Anestésicos Locales/efectos adversos , Antiinflamatorios/efectos adversos , Anticonvulsivantes/uso terapéutico , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Cefalalgia Histamínica/fisiopatología , Fructosa/análogos & derivados , Fructosa/uso terapéutico , Lateralidad Funcional/efectos de los fármacos , Lateralidad Funcional/fisiología , Trastornos de Cefalalgia/complicaciones , Trastornos de Cefalalgia/tratamiento farmacológico , Humanos , Hipotálamo/fisiología , Hipotálamo/fisiopatología , Lidocaína/efectos adversos , Masculino , Persona de Mediana Edad , Órbita/irrigación sanguínea , Órbita/inervación , Órbita/fisiopatología , Topiramato , Resultado del Tratamiento , Triamcinolona/efectos adversos , Núcleo Caudal del Trigémino/efectos de los fármacos , Núcleo Caudal del Trigémino/fisiopatologíaRESUMEN
An evaluation of potential adverse human health effects of disinfection byproducts requires study of both cancer and noncancer endpoints; however, no studies have evaluated the neurotoxic potential of a common haloacetic acid, dibromoacetic acid (DBA). This study characterized the neurotoxicity of DBA during 6-month exposure in the drinking water of rats. Adolescent male and female Fischer 344 rats were administered DBA at 0, 0.2, 0.6, and 1.5 g/l. On a mg/kg/day basis, the consumed dosages decreased greatly over the exposure period, with average intakes of 0, 20, 72, and 161 mg/kg/day. Weight gain was depressed in the high-concentration group, and concentration-related diarrhea and hair loss were observed early in exposure. Testing with a functional observational battery and motor activity took place before dosing and at 1, 2, 4, and 6 months. DBA produced concentration-related neuromuscular toxicity (mid and high concentrations) characterized by limb weakness, mild gait abnormalities, and hypotonia, as well as sensorimotor depression (all concentrations), with decreased responses to a tail-pinch and click. Other signs of toxicity at the highest concentration included decreased activity and chest clasping. Neurotoxicity was evident as early as one month, but did not progress with continued exposure. The major neuropathological finding was degeneration of spinal cord nerve fibers (mid and high concentrations). Cellular vacuolization in spinal cord gray matter (mostly) and in white matter (occasionally) tracts was also observed. No treatment-related changes were seen in brain, eyes, peripheral nerves, or peripheral ganglia. The lowest-observable effect level for neurobehavioral changes was 20 mg/kg/day (produced by 0.2 g/l, lowest concentration tested), whereas this dosage was a no-effect level for neuropathological changes. These studies suggest that neurotoxicity should be considered in the overall hazard evaluation of haloacetic acids.