Alejandro Hernández

Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats

To study the antinociceptive synergy resulting from the combination of opioid receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists on neuropathic pain, an isobolographic analysis of equianalgesic combinations of ketamine with methadone or morphine was performed in rats with mononeuropathy produced by placing four constrictive ligatures around the common sciatic nerve. Two weeks later, the antinociceptive effect of subcutaneous administration of the drugs alone or combined was evaluated by using the paw pressure test. Drugs and their combinations produced dose-dependent antinociception. Combinations produced synergy of a supra-additive nature in the neuropathic paw, but only additive antinociception in the normal paw. The ketamine/methadone combination was more effective to produce antinociception in the neuropathic paw than was the ketamine/morphine association, as revealed by the lower ED25. The results indicate supra-additive synergy between NMDA receptor antagonists and opioids, especially methadone, to produce antinociception in experimental neuropathy.

Involvement of spinal cord BDNF in the generation and maintenance of chronic neuropathic pain in rats

Brain-derived neurotrophic factor (BDNF) is involved in neuronal survival and synaptic plasticity of the central and peripheral nervous system. In chronic pain, plastic changes in dorsal horn neurons contribute to a phenomenon of hypersensitivity to pain sensation that is maintained over time, known as central sensitization. This process is accompanied by BDNF overexpression, but the role of BDNF in the generation and maintenance of the hyperalgesic phenomenon is still unclear. The present study was aimed to investigate if exogenous BDNF administered to the rat spinal cord, in addition to trigger pain, participates in the maintenance of the central sensitization process (i.e., pain persistence) and to determine if the pain generated is comparable to that observed in a neuropathic pain model. Results showed that a single intrathecal injection of 0.003 ng of BDNF was able to decrease the nociceptive threshold (Randall-Selitto test) in normal rats, for at least a 42-day period. Furthermore, the hyperalgesia generated was comparable to that observed in rats with a 42-day history of mononeuropathy. Increasing the dose or administering additional doses of BDNF resulted neither in additional effectiveness in reducing the pain threshold nor in the prolongation of the hyperalgesic effect, thus showing that central sensitization induced by BDNF is a dose-independent, all-or-none process. It is concluded that BDNF alone is sufficient for generating a long-lasting neural excitability change in the spinal cord via tyrosine kinase B receptor signaling, similar to that observed in chronic pain models such as neuropathy.

Cyclotraxin-B, a New TrkB Antagonist, and Glial Blockade by Propentofylline, Equally Prevent and Reverse Cold Allodynia Induced by BDNF or Partial Infraorbital Nerve Constriction in Mice

UNLABELLEDnSeveral lines of evidence indicate that brain-derived neurotrophic factor (BDNF) plays a key role as a central pronociceptive modulator of pain, acting through postsynaptic TrkB receptors that trigger intracellular signaling cascades leading to central sensitization. The overall aim of this study was to investigate to what extent BDNF could participate in the generation and maintenance of trigeminal neuropathic pain. The results showed that acute intracisternal administration of nanogram doses of BDNF in naïve mice elicited long-lasting, dose-related, cold allodynic responses to topical application of acetone onto vibrissal pad skin. The systemic administration of cyclotraxin-B (CTX-B), a new TrkB receptor antagonist, or propentofylline, an inhibitor of glial activation, was able to either prevent or reverse the effects of intracisternal BDNF on cold nociception. In addition, the blockade of TrkB receptor by CTX-B inhibited the mechanisms that either initiate or maintain cold allodynia in the ipsilateral vibrissal pad skin after unilateral constriction of the infraorbital nerve. These observations raise the possibility that BDNF is capable on its own of conveying many features of the signaling mechanisms that underlie central sensitization caused by nerve constriction.nnnPERSPECTIVEnAlthough further studies are necessary to examine in detail the mechanisms underlying the strong anti-allodynic action of CTX-B, this compound may represent an interesting lead for the development of novel therapeutic strategies aimed at preventing and/or suppressing central sensitization associated with neuropathic pain.

Antinociceptive effect of clomipramine in monoarthritic rats as revealed by the paw pressure test and the C-fiber-evoked reflex.

The antinociceptive effect of clomipramine was studied in monoarthritic rats by using the paw pressure test and the C-fiber-evoked reflex. Monoarthritis was produced by intra-articular injection of complete Freunds adjuvant into the tibio-tarsal joint. Joint circumference as well as vocalization threshold to graded paw pressure were evaluated weekly during a 14-week period after the intra-articular injection. At week 8, monoarthritic and vehicle-injected control rats were given either clomipramine or saline and both the paw pressure threshold and inhibition of the C-fiber-evoked reflex response were evaluated. Results showed that (i) 1.5, 3.0, and 6.0 mg/kg, i.v. of clomipramine induced significantly greater dose-dependent antinociception to paw pressure testing in the monoarthritic group, as compared to the control one; and (ii) 0.75, 1.5, 3.0, and 6.0 mg/kg, i.v. of clomipramine exerted significantly higher dose-dependent inhibition of the C-reflex activity in monoarthritic rats than in controls. Results suggest that the higher sensitivity to clomipramine in monoarthritic rats could be related to adaptive changes occurring in monoamine metabolism or in other neurotransmitter systems during chronic pain.

Effects of clomipramine and desipramine on a C-fiber reflex in rats

A C-fiber nociceptive reflex evoked by electrical stimulation within the territory of the sural nerve, was recorded from the ipsilateral biceps femoris muscle in urethane anesthetized rats. Intravenously administered clomipramine and desipramine produced a dose-dependent depression of the C-fiber reflex. High doses of intrathecal desipramine also inhibited the C-fiber reflex, while similar intrathecal doses of clomipramine produced only a modest inhibition of the response. Intracerebroventricular administration of clomipramine decreased dose-dependently the C-fiber reflex whereas intracerebroventricular desipramine increased this reflex. These findings suggest that tricyclic antidepressants with noradrenergic selectivity, as desipramine, inhibit the spinal processing of C inputs by acting directly at the spinal cord level, while those with serotonergic spectra, as clomipramine, depress the C-fiber-evoked spinal reflex by acting at a supraspinal modulatory site.

Lesion of the bulbospinal noradrenergic pathways blocks desipramine-induced inhibition of the C-fiber evoked nociceptive reflex in rats

Desipramine-induced inhibition of spinal cord nociceptive transmission was studied in rats with or without lesion of the bulbospinal noradrenergic system by recording the C-fiber evoked nociceptive reflex from a hind limb. Bulbospinal noradrenergic projections were lesioned by injecting intrathecally 20 microg of 6-hydroxydopamine 2 weeks before the electrophysiological experiments. Results show that desipramine (5, 10 and 20 mg/kg intraperitoneally) produced dose-dependent inhibition of the C reflex response duration in rats having intact noradrenergic bulbospinal systems. The inhibitory effect of desipramine was reduced or even abolished in rats pre-treated with 6-hydroxydopamine. In addition, [3H]-noradrenaline uptake was significantly lower in spinal cord slices arising from 6-hydroxydopamine lesioned animals, as compared to that from intact rats. These observations support the notion that the antinociceptive activity of antidepressants with noradrenergic selectivity depends on a normal rate of endogenous noradrenaline released by bulbospinal neurons.

Preference for high-fat diet is developed by young Swiss CD1 mice after short-term feeding and is prevented by NMDA receptor antagonists

Obesity is a worldwide epidemic that is increasing at an alarming rate. One of its causes is the increased availability and consumption of diets rich in fat. In the present study, we investigated the effects of short-term consumption of a high fat diet (HFD) on dietary preferences in Swiss CD1 mice and its relation in time to specific metabolic effects. Mice that were weaned 21days postpartum and fed a chow diet for one week were afterward subjected to a diet preference test for 5days, exposed to both a regular diet (RD) and HFD. We found that mice did not show any preferences. In a second experiment, two groups of mice that were weaned 21days postpartum and subjected to a chow diet for one week were fed either RD or HFD for 18days, and a diet preference test was performed for 5days. After this short-term consumption of HFD, mice preferred HFD, while mice subjected to RD did not show any preference. Importantly, no differences in blood glucose levels were found between the groups prior to and after the experiments. The results support our hypothesis that the preference for HFD is not a spontaneous behavior in CD1 mice, but it can be observed after short-term consumption; additionally, this preference develops before metabolic effects appear. Finally, this preference for HFD could not be observed when the mice were i.p. injected daily with low doses of the NMDA receptor antagonists, ketamine, ifenprodil or MK-801 during the HFD feeding period. These data suggest that acquisition of dietary preference for HFD is a NMDA receptor-dependent learning process.

Efecto de la Desnutrición Oculta Prenatal Sobre la Histología del Esplenio Callosal

Ratas malnutridas prenatalmente con una dieta isocalorica y baja en proteinas, presentaron un menor diametro axonal promedio en el esplenio callosal que los animales control, tanto de las fibras mielinicas como amielinicas. Tambien se observo una mayor densidad axonal promedio, con respecto a los controles. Estas observaciones sugieren que: 1) las conexiones cortico-corticales (interhemisfericas) son vulnerables a la malnutricion proteica; y 2) lo anterior tendria incidencia en la velocidad de conduccion interhemisferica, en particular con lo que dice relacion con las conexiones visuales

Anatomy of corpus callosum in prenatally malnourished rats

The effect of prenatal malnutrition on the anatomy of the corpus callosum was assessed in adult rats (45-52 days old). In the prenatally malnourished animals we observed a significant reduction of the corpus callosum total area, partial areas, and perimeter, as compared with normal animals. In addition, the splenium of corpus callosum (posterior fifth) showed a significant decrease of fiber diameters in the myelinated fibers without changing density. There was also a significant decrease in diameter and a significant increase in density of unmyelinated fibers. Measurements of perimeters fractal dimensions from sagittal sections of the brain and corpus callosum did not show significant differences between malnourished and control animals. These findings indicate that cortico-cortical connections are vulnerable to the prenatal malnutrition, and suggest this may affect interhemispheric conduction velocity, particularly in visual connections (splenium).

Densidad Neuronal en la Corteza Visual Primaria (Área 17), en Ratas Sometidas a Estrés Crónico

El estres puede ser definido como una amenaza a la integridad psicologica o fisiologica de un individuo. Por otro lado, se ha verificado que el estres tiene efecto sobre la morfologia y funcion de diversas estructuras del Sistema Nervioso Central, relacionadas con el aprendizaje, memoria y respuestas emocionales, tales como el hipocampo, amigdala y corteza prefrontal. Es por lo anterior, que el objetivo del presente trabajo fue realizar un estudio de la anatomia de la corteza visual primaria (area 17), en ratas machos (n=9), de la cepa Sprague-Dawley, de 3 meses de edad (250-350g.), sometidas a estres cronico por inmovilizacion. Es asi como se observo que el grupo estres (n=3) presento una menor densidad neuronal que el grupo control (n=3) y una significativa menor densidad neuronal (p<0,05) que el grupo postestres (n=3) el cual presento la mas alta densidad neuronal observada. Estableciendo una relacion inversa entre densidad neuronal y tamano de los somas neuronales y sus respectivas conexiones y ramificaciones dendriticas. Lo anterior podria tener incidencia en el procesamiento de la informacion visual.