Extracellular signal-regulated kinase activation in the chronic constriction injury model of neuropathic pain in anaesthetized rats.

BACKGROUND: The role of extracellular signal-regulated kinases (ERKs) in nociception has been explored in the last years. While in spinal cord their activation is frequently correlated with pain or acute noxious stimuli, supraspinally, this association is not so evident and remains unclear. This study aims to evaluate ERK1/2 activation in the spinal cord and brainstem nuclei upon neuropathy and/or an additional mechanical stimulus. METHODS: Acute noxious mechanical stimulation was applied in the left hindpaw of anaesthetized SHAM-operated and chronic constriction injured (CCI, neuropathic pain model) rats. Other SHAM or CCI rats did not receive any stimulus. Immunohistochemistry against the phosphorylated isoforms of ERK1/2 (pERK1/2) was performed in lumbar spinal cord and brainstem sections to assess ERK1/2 activation. RESULTS: In the spinal cord, stimulation promoted an increase in pERK1/2 expression in the superficial dorsal horn of SHAM rats. No significant effects were caused by CCI alone. At supraspinal level, changes in ERK1/2 activation induced by CCI were observed in A5, locus coeruleus (LC), raphe obscurus (ROb), raphe magnus, dorsal raphe (DRN), lateral reticular and paragigantocellularis nucleus. CCI increased pERK1/2 expression in all these nuclei, with exception of LC, where a significant decrease was verified. Mechanical noxious stimulation of CCI rats decreased pERK1/2 expression in ROb and DRN, but no further changes were detected in either SHAM- or CCI-stimulated animals. CONCLUSION: ERK1/2 are differentially activated in the spinal cord and in selected brainstem nuclei implicated in nociception, in response to an acute noxious stimulus and/or to a neuropathic pain condition.

[Analysis of gastric emptying dynamics in relationship to qualitative composition of intake. Comparison between normal-weight and obese subjects]. / Análisis de la dinámica de vaciamiento gástrico en relación con la composición cualitativa de la ingesta. Comparación entre sujetos con normopeso y obesos.

AIMS: To analyze whether the gastric emptying profile could define obesity and to study the impact of macronutrients diet composition on gastric emptying in obese and non obese people. MATERIAL AND METHODS: 47 subjects were selected (12 non obese and 35 obese). The study was organized in 4 visits. In each visit the subject was given isocaloric breakfast differing in macronutrient composition, (either equilibrated, or lipid, protein or carbohydrate rich) quantitative gastric emptying assay was done realized, every 15 minutes for two hours using a radionuclide technique. The week prior to the visit, the subject followed a standard 1,800 cal/day diet. RESULT: A significant interaction between time and diet composition is shown regardless of the group (obese or non-obese) the subject belongs to. The different macronutrient composition differentially affected gastric emptying only in the obese group. Post hoc analysis of the results showed significant differences after 45 min post breakfast between protein and carbohydrate rich breakfast. CONCLUSIONS: Gastric emptying in obese but not in non obese subjects, was significantly modified depending on the intake qualitative composition. These differences are clear when protein rich (significantly slower emptying) is compared versus hydrocarbon enriched diet (significantly faster emptying). A significant difference in gastric emptying between obese and non-obese subjects cannot be established.

Análisis de la dinámica de vaciamiento gástrico en relación con la composición cualitativa de la ingesta. Comparación entre sujetos con normopeso y obesos / Analysis of gastric emptying dynamics in relationship to qualitative composition of intake. Comparison between normal weight and obese subjects

Objetivos. Analizar si el perfil de vaciamiento gástrico podría ser característico en obesidad y estudiar el impacto que la relación de macronutrientes en la dieta tiene sobre el vaciamiento gástrico y las diferencias entre obesos y normopesos. Material y método. Se seleccionan 47 sujetos (12 normopeso y 35 obesos), que realizan 4 visitas durante el estudio. En cada una se administraba un desayuno isocalórico con distinta composición de macronutrientes (equilibrados, lipídico, proteico o hidrocarbonato). Se realizaron estudios cuantitativos de vaciamiento gástrico cada 15 minutos durante dos horas usando la técnica de gammagrafía. La semana previa a cada visita todos los sujetos realizaron una dieta estándar de 1.800 cal/día. Resultados. Se observa una interacción significativa entre los factores tiempo y dieta. Sin embargo, el mismo análisis no demostró esta tendencia al estudiar la evolución del vaciamiento en relación con el grupo al que pertenecía el sujeto (normopeso u obeso). La composición cualitativa de la dieta sólo influyó sobre el vaciamiento gástrico en obesos. El estudio post hoc demostró diferencias significativas fundamentalmente a partir de los 45 minutos postingesta, y entre ingestas ricas en hidratos de carbono y proteínas. Conclusiones. La composición cualitativa de la ingesta ha influido de forma significativa sobre la velocidad de vaciamiento gástrico en sujetos obesos, pero no en normopesos. Esta influencia se hace más evidente en la dieta hidrocarbonada (vaciamiento significativamente más rápido) y proteica (vaciamiento significativamente más lento). No puede establecerse una diferencia significativa de la velocidad de vaciamiento gástrico entre sujetos obesos o normopeso

Aims. To analyze whether the gastric emptying profile could define obesity and to study the impact of macronutrients diet composition on gastric emptying in obese and non obese people. Material and methods. 47 subjects were selected (12 non obese and 35 obese). The study was organized in 4 visits. In each visit the subject was given isocaloric breakfast differing in macronutrient composition, (either equilibrated, or lipid, protein or carbohydrate rich) quantitative gastric emptying assay was done realized, every 15 minutes for two hours using a radionuclide technique. The week prior to the visit, the subject followed a standard 1,800 cal/day diet. Result. A significant interaction between time and diet composition is shown regardless of the group (obese or non obese) the subject belongs to. The different macronutrient composition differentialy affected gastric emptying only in the obese group. Post hoc analysis of the results showed significant differences after 45 min post breakfast between protein and carbohydrate rich breakfast. Conclusions. Gastric emptying in obese but not in non obese subjects, was significantly modified depending on the intake qualitative composition. These differences are clear when protein rich (significantly slower emtying) is compared versus hydrocarbon enriched diet (significantly faster emptying). A significant difference in gastric emptying between obese and non obese subjects cannot be stablished

Interactions of acute morphine with chronic imipramine and fluvoxamine treatment on the antinociceptive effect in arthritic rats.

This study was undertaken to investigate the effects induced by chronic systemic administration of two different antidepressants: imipramine (IMI), a dual serotonin-noradrenaline reuptake inhibitor, and fluvoxamine (FVX), a selective serotonin reuptake inhibitor, on the antinociceptive effect of morphine (MOR) in a paw pressure test in adjuvant-induced arthritic rats. For 30 days rats were administered with IMI, FVX or saline (SAL). On days 15 and 30, animals were tested in the paw pressure test 20 min after MOR or SAL administration. MOR induced a significant antinociceptive effect in IMI, FVX and SAL treated rats. But, at 30 days, this increase in pain threshold was significatively higher in IMI than SAL rats. This increase was not seen in FVX rats. These results suggest that a combination of opioid and mixed monoaminergic activities is effective in enhancing the antinociceptive effect of MOR in arthritic rats while only opioid and serotonergic activities have no enhancer effect.

Farmacología de la analgesia inducida por el trasplante de médula suprarrenal en el espacio subaracnoideo lumbar de la rata. fundamentos y aproximación clínica / Pharmacology of the analgesia induced by the transplantation of suprarenal medulla to the lumbar subarachnoid space in rats. Foundations and clinical approach

El trasplante de tejido de médula suprarrenal en el espacio subaracnoideo lumbar de la rata es una prometedora herramienta terapéutica para el tratamiento del dolor. El funcionamiento del trasplante se basa en la liberación de péptidos opioides y catecolaminas por parte de las células cromafines en el líquido cefalorraquídeo espinal. Desde ahí estas sustancias pueden ejercer su acción sobre los receptores opioides y adrenérgicos existentes en el asta dorsal de la médula espinal. En algunos casos, el efecto analgésico observado en los tests algesiométricos agudos en la rata ha sido facilitado mediante la estimulación de la liberación de las sustancias neuroactivas con nicotina, mientras que en modelos experimentales de dolor crónico no es necesaria. Este efecto analgésico ha sido antagonizado por naloxona y por fentolamina. En nuestro laboratorio hemos mejorado el efecto analgésico con el tratamiento con amitriptilina y con un inhibidor de la degradación de los péptidos opioides endógenos En clínica se han dado los primeros pasos para la utilización de esta técnica en pacientes con dolor por cáncer terminal. En ellos se han conseguido resultados esperanzadores tanto en el alivio del dolor como en la reducción del tratamiento complementario con opiáceos (AU)

Antinociception produced by the peptidase inhibitor, RB 101, in rats with adrenal medullary transplant into the spinal cord.

This study was undertaken to investigate the effects induced by the systemic administration of RB 101 [N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxoprpyl]-L-phenylalanine benzyl ester], a mixed inhibitor of the enkephalin catabolism able to cross the blood-brain barrier, in antinociception produced by adrenal medullary tissue transplanted in the rat spinal subarachnoid space. For this purpose, the antinociceptive responses induced by intravenous (i.v.) administration of RB 101 were evaluated in the tail-flick in rats transplanted 28 and 56 days before the test. Systemic administration of RB 101 induced antinociceptive effects in sham-operated rats, as previously reported. RB 101 also enhanced significantly the antinociception produced by the autotransplant 28 and 56 days after surgery. The antinociceptive responses of RB 101 in both sham-operated and autotransplanted rats were blocked by naloxone, but were not modified by the noradrenergic antagonist, phentolamine, suggesting a selective involvement of opioid mechanisms. The present results indicate that the inhibitors of enkephalin catabolism enhance the antinociception induced by adrenal medullary transplants.

The effects of different monoaminergic antidepressants on the analgesia induced by spinal cord adrenal medullary transplants in the formalin test in rats.

We studied the effects of chronic intraperitoneal administration of antidepressants on the antinociception induced by adrenal medullary transplants into the subarachnoid space in rats using the formalin test. Administration of drugs started 28 days after operation and the formalin test was performed on Day 56. When amitriptyline (AMT; 15 mg x kg(-1) x day(-1)) was administered to sham-operated rats, it decreased the licking time and increased the transplant-induced analgesia in Phase 1 when administered to transplanted rats. Chronic treatment with fluvoxamine (FVX, 10 mg x kg(-1) x day(-1)) had no influence on the licking response in sham rats, nor did it modify the transplant-induced analgesia when administered to transplanted rats. When desipramine (DMI; 10 mg x kg(-1) x day(-1)) was administered to sham rats, it significantly reduced the licking response in Phase 1, but when administered to transplanted rats it did not increase the transplant-induced analgesia. None of the drugs administered showed any effect on Phase 2 of the formalin test. These results suggest that adrenal medullary transplants into the spinal cord induce analgesia as determined by the formalin test. This effect is more pronounced when AMT (a nonselective noradrenaline-serotonin reuptake inhibitor) is chronically administered, but not when FVX or DMI are chronically administered.

[Amitriptyline facilitates the analgesic effect of adrenal medulla autograft in the lumbar subarachnoid space of the rat]. / La amitriptilina facilita el efecto analgésico del autotrasplante de médula suprarrenal en el espacio subaracnoideo lumbar de la rata.

OBJECTIVES: To investigate the possible enhancement of analgesic effect induced by treatment with amitriptyline (AMI) after the autografting of suprarenal medulla into the subarachnoid lumbar space in the rat. MATERIAL AND METHODS: Four experimental groups were formed (control + saline solution [SS]; control + AMI; transplant + SS and transplant + AMI). AMI (10 mg/kg i.p.) or SS was administered for 28 days after surgery. The tail-flick test, with baseline values taken before surgery, was used to measure threshold pain on days 1, 4, 7, 14, 21 and 28. RESULTS: Suprarenal medullae transplantation afforded evident analgesic effect from day 1 to day 28. Analgesic effect was enhanced in transplanted rats treated with AMI from day 4 of treatment, with more evident effect on day 28. No analgesic effect per se was observed in the control group. CONCLUSIONS: Our results confirm that grafting per se has an analgesic effect and that it can be improved by systematic treatment with AMI. These results suggest new possibilities for using suprarenal medulla grafts for pain.

Effect of amitriptyline on the analgesia induced by adrenal medullary tissue transplanted in the rat spinal subarachnoid space as measured by an experimental model of acute pain.

The effect of short and long term amitriptyline (AMI) treatment on the analgesia induced by adrenal medullary autotransplant into the subarachnoid space was investigated in rats. For this purpose, two experiments were carried out. In the first one, the rats were chronically treated for 28 days after transplantation. In the second experiment, rats were treated for 28 days starting 28 days after surgery. Before starting the experiments, basal levels were tested. Tail-flick latencies were checked at Day 4 and Day 28 in the first experiment and at Day 28 and Day 56 in the second. AMI itself did not induce any tail-flick modification after 28 or 56 days. However, it increased the transplantation-induced analgesia at Day 28 in the first experiment and at Day 56 in the second. These results are interpreted in the sense of the ability of AMI to enhance the effects of both monoamine and opioids previously released by the transplantation.

Antinociceptive effects of phenobarbital in "tail-flick" test and deafferentation pain.

Deafferentation pain has been related to abnormal electrical hyperactivity in the neurons of the sensory relays in the central nervous system. This electrical activity resembles the epileptoid pattern observed in experimental epileptoid foci. With the aim of preventing this hyperactivity, rats were given long-term treatment with phenobarbital after sciatic transection and dorsal cervical rhizotomy. Daily intramuscular injections of saline solution or 5 and 10 mg/kg of phenobarbital were administered for 20 days, starting 10 days before surgery. Larger doses of phenobarbital delayed the onset and reduced the severity of autotomy. In a test of acute pain, the effect of intraperitoneal (1-16 mg) and intrathecal (100-500 micrograms) phenobarbital was studied by measuring the "tail-flick" response latency. Intraperitoneal phenobarbital did not modify acute pain, but 500 micrograms of intrathecal phenobarbital increased the threshold of pain. These results indicate that (a) phenobarbital, a drug with anticonvulsant activity, reduces deafferentation behavior in rats, and (b) intrathecal phenobarbital has an antinociceptive action in acute experimental pain.