Cortisol affects pain sensitivity and pain-related emotional learning in experimental visceral but not somatic pain: a randomized controlled study in healthy men and women.

Despite growing interest in the role of stress mediators in pain chronicity, the effects of the stress hormone cortisol on acute pain remain incompletely understood. In a randomized, double-blind, placebo-controlled study with N = 100 healthy volunteers, we tested the effects of oral hydrocortisone (20 mg) in 2 widely used pain models for the visceral and somatic modality. Salivary cortisol was increased in the hydrocortisone group (time × group: P < 0.001). For the visceral modality, assessed using pressure-controlled rectal distensions, hydrocortisone decreased the pain threshold from before to after treatment (time × group: P = 0.011), an effect primarily driven by women (time × sex: P = 0.027). For the somatic modality, cutaneous heat pain thresholds remained unaffected by hydrocortisone. Hydrocortisone did not alter perceived pain intensity or unpleasantness of either modality. Conditioned pain-related fear in response to predictive cues was only observed for the visceral modality (time × modality: P = 0.026), an effect that was significantly reduced by hydrocortisone compared with placebo (time × group: P = 0.028). This is the first psychopharmacological study to support that acutely increased cortisol enhances pain sensitivity and impairs pain-related emotional learning within the visceral, but not the somatic pain modality. Stress-induced visceral hyperalgesia and deficits in emotional pain-related learning could play a role in the pathophysiology of chronic visceral pain.

Are there sex differences in visceral sensitivity in young healthy men and women?

BACKGROUND: Visceral hypersensitivity plays a key role in the pathophysiology of chronic visceral pain like irritable bowel syndrome (IBS), which is significantly more prevalent in women. Possible sex differences in visceral sensitivity remain poorly studied. We assessed sex differences in visceral sensitivity and their association with subclinical symptoms, trait anxiety, and chronic stress in a large sample of healthy men and women. METHODS: In 280 young healthy volunteers (50% female), visceral sensory and pain thresholds were determined using rectal balloon distensions. Gastrointestinal (GI) symptoms, chronic stress, and trait anxiety as IBS-related risk factors were assessed with questionnaires. Men and women were compared regarding visceral sensitivity and multiple regression analyses were conducted to evaluate the predictive value of sex and risk factors for visceral sensitivity. Subgroups with high, intermediate, and low sensitivity were compared regarding psychological and biological characteristics. KEY RESULTS: Men and women did not differ in sensory or pain thresholds or in IBS-related risk factors. In multiple regression analyses, no predictor of visceral sensitivity could be identified. While sensitivity subgroups differed in sensory and pain thresholds, the proportions of men and women were comparable, and groups did not differ in IBS-related risk factors. CONCLUSIONS AND INFERENCES: Despite the large sample size, we found no evidence supporting sex differences in visceral sensitivity. At least in healthy young volunteers, our findings suggest that sex, GI symptoms, anxiety, or chronic stress do not contribute to altered visceral sensitivity.

Left dominance for language perception starts in the extrastriate cortex: An ERP and sLORETA study.

While it is well known that the left hemisphere is more efficient than the right in most tasks involving perception of speech stimuli, the neurophysiological pathways leading to these lateralised performance differences are as yet rather unclear. In particular, the question whether language lateralisation depends on semantic processing or is already evident in early perceptual stimulus processing has not been answered unequivocally. In the present study, we therefore recorded event-related potentials (ERPs) during tachistoscopic presentation of horizontally or vertically presented verbal stimuli in the left (LVF) and the right visual field (RVF). Participants were asked to indicate, whether the presented stimulus was a word or a non-word. On the behavioural level, participants showed stronger hemispheric asymmetries for horizontal, than for vertical stimulus presentation. In addition, ERP asymmetries were also modulated by stimulus presentation format, as the electrode by visual field interactions for P1 and N1 were stronger after vertical, than after horizontal stimulus presentation. Moreover, sLORETA revealed that ERP left-right asymmetries were mainly driven by the extrastriate cortex and reading-associated areas in the parietal cortex. Taken together, the present study shows electrophysiological support for the assumption that language lateralisation during speech perception arises from a left dominance for the processing of early perceptual stimulus aspects.

Stereochemical comparison of nebivolol with other beta-blockers.

beta-Blockers are widely used in the treatment of cardiovascular disease and act by antagonizing the effects of adrenaline (epinephrine) and noradrenaline (norepinephrine) on beta-adrenergic receptors. All beta-blockers currently used in the treatment of cardiovascular disease contain at least one chiral center and, while most are marketed as racemates, their cardiac antihypertensive activity generally resides in the S-enantiomer. Nebivolol is a third generation beta-blocker that is highly selective for the beta(1)-adrenoceptor. The nebivolol molecule contains four chiral centers and is marketed as a racemate of (+)-nebivolol (SRRR-configuration) and (-)-nebivolol (RSSS-configuration). Nebivolol differs from all other beta-blockers with a hydroxypropanolamine substructure in that its cardiac antihypertensive activity resides in the R-enantiomer at the hydroxy group, whereas all other beta-blockers have antihypertensive activity in the S-enantiomer. Two of the four chiral centers in nebivolol are part of a ring structure and the increased rigidity of this structure may be related to nebivolol's divergence from the standard pharmacophore model of beta-blockers.

Synthesis of thieno[2,3-b]pyridinones acting as cytoprotectants and as inhibitors of [3H]glycine binding to the N-methyl-D-aspartate (NMDA) receptor.

The standard glycine site antagonist of the N-methyl-D-aspartate (NMDA) receptor, 3-phenyl-4-hydroxyquinolin-2(1H)-one (21), was used as a template for bioisostere benzene/thiophene exchange. Phenylacetylation of aminothiophene carboxylic acid methyl esters and subsequent cyclization delivered the three possible thienopyridinone isomers. 4-Hydroxy-5-phenylthieno[2,3-b]pyridin-6(7H)-one (3a), with the shortest distance between the sulfur and the nitrogen atom, was the most potent isomer (K(i) against the binding of [(3)H]glycine to rat membranes 16 microM), comparable in potency to the model quinolinone (21, 12 microM). Replacement of the phenyl substituent of 21 by a 2-thienyl residue resulted in a 2-5-fold loss in potency and was abandoned. In the thieno part of the thienopyridinone nucleus, the most successful substituents were halogen (Cl or Br) close to the sulfur atom and short alkyl chains at the other position, resulting in 7h, 8h, 8i, and 8m, with K(i) values between 5.8 and 10.5 nM. Introduction of a 3'-phenoxy moiety yielded several compounds with still higher potencies (18h, 18i, 18l, and 18m; K(i) between 1.1 and 2.0 nM). Quantitative structure-activity relationship (QSAR) calculations resulted in a consistent interpretation of the potencies of most compounds. Several of these 3'-phenoxy derivatives protected mouse fibroblast cell lines with transfected NMDA receptors from glutamate-induced toxicity. In addition, we report in vivo results for four of these compounds.

Stereoisomers of compounds with symmetric constitutions.

Chiral organic compounds with unsymmetric constitutions can lead to N(r) = 2(n) stereoisomers. By contrast, if a chiral compound has a symmetric constitution, then the number of stereoisomers is reduced. In this publication, we wish to present an algorithm to calculate the number of stereoisomers of chiral organic compounds of the latter type (e. g. sugar acids). The first step is the development of two different functions for unbranched compounds where the number of repeating units is even or uneven. Other stereogenic units like double bonds, chiral axes or planes are not discussed. The results are then checked against the actual isomers. The next step leads to a unified equation to predict the precise number of stereoisomers that can exist. Thus, the relationship between chirality and symmetry is shown in detail. Additionally, the algorithm is applied to some drug molecules with symmetric constitutions.