Bilateral subdiaphragmatic vagotomy modulates the peripheral met­enkephalin and striatal monoamine responses to peripheral inflammation in rat.

In the central nervous system, long­term effects of a vagotomy include disturbance of monoaminergic activity of the limbic system. Since low vagal activity is observed in major depression and autism spectrum disorder, the study aimed to determine whether animals fully recovered after subdiaphragmatic vagotomy demonstrates neurochemical indicators of altered well­being and social component of sickness behavior. Bilateral vagotomy or sham surgery was performed in adult rats. After one month of recovery, rats were challenged with lipopolysaccharide or vehicle to determine the role of central signaling upon sickness. Striatal monoamines and met­enkephalin concentrations were evaluated using HPLC and RIA methods. We also defined a concentration of immune­derived plasma met­enkephalin to establish a long­term effect of vagotomy on peripheral analgesic mechanisms. The data indicate that 30 days after vagotomy procedure, striatal dopaminergic, serotoninergic, and enkephalinergic neurochemistry was altered, both under physiological and inflammatory conditions. Vagotomy prevented inflammation­induced increases of plasma met­enkephalin - an opioid analgesic. Our data suggest that in a long perspective, vagotomized rats may be more sensitive to pain and social stimuli during peripheral inflammation.

Effect of selective cyclooxygenase inhibitors on animal behaviour and monoaminergic systems of the rat brain.

The long-term effects of cyclooxygenase 1 and 2 (COX-1/2) inhibitors are usually tested in terms of the periphery of the organism. Therefore, we studied the effects of SC560 (selective COX-1 inhibitor) and celecoxib (selective COX-2 inhibitor) on the activity of brain monoaminergic systems and animal behaviour. Additionally, we tested the effect of these inhibitors during inflammation. We have observed that long-term administration of celecoxib reduces the activity of the noradrenergic system, increases the activity of dopaminergic and serotonergic systems, increases locomotor activity, and enhances the exploratory behaviour of rats. Administration of SC560 also increases the activity of dopaminergic and serotonergic systems but reduces locomotor activity and impairs the exploratory behaviour of rats. The mechanism responsible for decreased activity of the noradrenergic system may be related to the weakening of activity of the positive feedback loop between the paraventricular nucleus and coeruleus locus. We suggest that the effect of used inhibitors on the dopaminergic system is associated with a possible increase in anandamide concentration and its effect on dopamine reuptake in synaptic clefts. It also appears that cyclooxygenase peroxidase activity may play a role in this process. In turn, changes in the activity of the serotonergic system may be related to the activity of indoleamine-2,3-dioxygenase, which decreases because of the decreased concentration of pro-inflammatory compounds. We believe that behavioural changes induced by COX inhibitors are the result of the modified activity of monoaminergic CNS systems in the brainstem, hypothalamus, and medial prefrontal cortex.

Peripheral and central compensatory mechanisms for impaired vagus nerve function during peripheral immune activation.

BACKGROUND: Determining the etiology and possible treatment strategies for numerous diseases requires a comprehensive understanding of compensatory mechanisms in physiological systems. The vagus nerve acts as a key interface between the brain and the peripheral internal organs. We set out to identify mechanisms compensating for a lack of neuronal communication between the immune and the central nervous system (CNS) during infection. METHODS: We assessed biochemical and central neurotransmitter changes resulting from subdiaphragmatic vagotomy and whether they are modulated by intraperitoneal infection. We performed a series of subdiaphragmatic vagotomy or sham operations on male Wistar rats. Next, after full, 30-day recovery period, they were randomly assigned to receive an injection of Escherichia coli lipopolysaccharide or saline. Two hours later, animal were euthanized and we measured the plasma concentration of prostaglandin E2 (with HPLC-MS), interleukin-6 (ELISA), and corticosterone (RIA). We also had measured the concentration of monoaminergic neurotransmitters and their metabolites in the amygdala, brainstem, hippocampus, hypothalamus, motor cortex, periaqueductal gray, and prefrontal medial cortex using RP-HPLC-ED. A subset of the animals was evaluated in the elevated plus maze test immediately before euthanization. RESULTS: The lack of immunosensory signaling of the vagus nerve stimulated increased activity of discrete inflammatory marker signals, which we confirmed by quantifying biochemical changes in blood plasma. Behavioral results, although preliminary, support the observed biochemical alterations. Many of the neurotransmitter changes observed after vagotomy indicated that the vagus nerve influences the activity of many brain areas involved in control of immune response and sickness behavior. Our studies show that these changes are largely eliminated during experimental infection. CONCLUSIONS: Our results suggest that in vagotomized animals with blocked CNS, communication may transmit via a pathway independent of the vagus nerve to permit restoration of CNS activity for peripheral inflammation control.

31P double-quantum solid-state NMR study of phosphoroorganic compounds with (O)P-O-P-(O), (S)P-O-P(S) and (S)P-S-P(O) unit.

In this work we have tested applicability of the commonly used double quantum recoupling sequence POST-C7 to study of (31)P-(31)P geometrical constraints for phosphoroorganic model compounds with different chemical shift anisotropy (CSA) and distinct molecular dynamics in the crystal lattice. Our results clearly show that even with large CSA, POST-C7 gives good efficiency of (31)P double-quantum excitations. Moreover, large amplitude molecular motion only slightly disturb (31)P build-up curve. Chi(2) error analysis is used for verification of values and orientations of chemical shift tensors (CST) parameters employed for simulation of POST-C7 buildup curves.

Study of molecular dynamics and the solid state phase transition mechanism for unsymmetrical thiopyrophosphate using X-ray diffraction, DFT calculations and NMR spectroscopy.

Differential scanning calorimetry (DSC) and low-temperature X-ray diffraction studies showed that 2-thio-(5,5-dimethyl-1,3,2-dioxaphosphorinanyl)2'-oxo-dineopentyl-thiophosphate (compound 1) undergoes reversible phase transition at 203 K related to the change of symmetry of the crystallographic unit. Solid state NMR spectroscopy was used to establish the dynamic processes of aliphatic groups and the phosphorus skeleton. 13C and 31P variable temperature NMR studies as well as T1 and T1rho measurements of relaxation times revealed the different mode of molecular motion for each neopentyl residue directly bonded to phosphorus. It is concluded that molecular dynamics of aliphatic groups causes different van der Waals interactions in the crystal lattice and is the driving force of phase transition for compound 1. Finally, we showed that very sharp phase transition temperature makes compound 1 an excellent candidate as a low-temperature NMR thermometer in the solid phase.