Neuroscience
-
N-methyl-D-aspartate receptor activation regulates refractoriness of status epilepticus to diazepam.
Status epilepticus, prolonged intermittent or continuous seizure activity lasting 30 min or longer, is associated with high morbidity and mortality. The longer a seizure persists, the more refractory to treatment it becomes. The pilocarpine model of status epilepticus in rodents develops refractoriness to many first-line treatments as seizure duration increases, rendering it a good model to study refractory status epilepticus. ⋯ The results indicate that N-methyl-D-aspartate receptor activation plays a role in the seizure-induced refractoriness to benzodiazepines in status epilepticus, and blocking N-methyl-D-aspartate receptor activation converts refractory status epilepticus to a seizure responsive to benzodiazepine therapy. These findings offer insights into developing novel therapeutic interventions to improve the treatment of status epilepticus. Understanding the molecular mechanisms that mediate the effects of N-methyl-D-aspartate receptor activation on the development of resistance to treatment in status epilepticus will provide rational insights into more rapid methods to terminate seizure activity in this condition.
-
We investigated the hypothesis that the Ca2+-activated protease calpain is involved in the pathophysiology of spinal cord injury, and is linked to the proteolytic degradation of cytoskeletal proteins. We report here that levels of calpain I (mu-calpain)-mediated spectrin breakdown products are increased by 15 min post-injury, with peak levels reached by 2 h post-injury. The dephosphorylated form of the neurofilament protein NF200 is substantially lost over the same time-period. ⋯ Densitometric analyses confirmed that loss of NF200 is a substrate-specific phenomenon, since (i) dephosphorylated NF200 was preferentially lost while phosphorylated NF200 was relatively spared, and (ii) actin, which is not a substrate for calpain, was relatively spared following spinal cord injury. Finally, we demonstrated calpain I-mediated spectrin breakdown within NF200-positive neuronal processes post-injury. We conclude that the accumulation of spectrin breakdown products is temporally and spatially correlated with loss of dephosphorylated NF200 after spinal cord injury.
-
Inflammation of peripheral tissues evokes spontaneous pain and an increased responsiveness to external stimuli known as hyperalgesia, produced by both peripheral and central changes. The central component is initiated by a sustained afferent barrage produced by sensitized peripheral nociceptors, but it is unclear to which extent ongoing nociceptive input is required to maintain these central changes. Here, we have used an isolated preparation of the spinal cord in vitro obtained from eight- to 12-day-old rats to examine spinal plasticity in the absence of naturally occurring afferent inputs. ⋯ In contrast, maximal behavioural hyperalgesia was observed by 3 h post-carrageenan, and thermal hyperalgesia had resolved by 20 h, although mechanical hyperalgesia remained. These results show that the induction of spinal plasticity independent of peripheral input is a progressive process with a slow time-course, since significant hyperreflexia in the isolated spinal preparation appears 6 h after inflammation and develops further within 20 h. We conclude that during the first 3 h following inflammation, hyperalgesia is the result of peripheral sensitization and of central mechanisms that depend on an ongoing peripheral input and thus changes were not observed in the isolated spinal cord.
-
In previous studies we have shown that electrical stimulation of the nucleus submedius inhibits the rat radiant heat-induced tail flick reflex, and that this antinociceptive effect is mediated by the ventrolateral orbital cortex and periaqueductal gray. The aim of the present study was to examine whether electrical stimulation of the nucleus submedius could inhibit the rat jaw-opening reflex, and to determine whether electrolytic lesions of the ventrolateral orbital cortex or the periaqueductal gray could attenuate the nucleus submedius-evoked inhibition. Experiments were performed on pentobarbital-anesthetized rats. ⋯ The onset of inhibition occured 60 ms after the beginning of nucleus submedius stimulation and lasted about 100 ms, as determined by varying the conditioning-test time interval. Furthermore, ipsilateral lesions of the ventrolateral orbital cortex or bilateral lesions of the lateral or ventrolateral parts of periaqueductal gray eliminated the nucleus submedius-evoked inhibition of the jaw-opening reflex. These data suggest that the nucleus submedius plays an important role in modulation of orofacial nociception, and provide further support for a hypothesis that the antinociceptive effect of nucleus submedius stimulation is mediated by ventrolateral orbital cortex and activation of a descending inhibitory system in the periaqueductal gray.
-
The amygdala is a complex forebrain structure proposed to play a pivotal role in fear conditioning circuitry. In this study, c-Fos immunomapping was applied to investigate the functional activation of particular amygdalar nuclei following a 50-trial training session of two-way active avoidance reaction. To dissect distinctive responses displayed by the animals and to cluster them into groups of correlated behaviors, factor analysis was employed. ⋯ The expression in the cortical nucleus correlated negatively with grooming behavior, whereas c-Fos immunolabeling of the other three subdivisions of the amygdala could be associated with the number of intertrial responses. No correlation was observed between c-Fos expression and avoidance reactions performed or the amount of shock received by the animal. The results obtained with c-Fos mapping of various regions of rat amygdala, combined with a fine dissection of behavioral repertoire, imply that there are specific functional links between particular parts of the structure and distinctive behaviors that reflect various emotional states of the animal.