Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1)

Peer reviewe

Tachykininergic and serotonergic control of the migrating motor complex : Studies in rat and man

TACHYKININERGIC AND SEROTONERGIC CONTROL OF THE MIGRATING MOTORCOMPLEX Studies in rat and man Mikael Lördal Department of Gastroenterology and Hepatology, Karolinska Hospital,Karolinska Institute Stockholm, Sweden Small bowel motility has been studied in rats and in humans by means of electromyographyand manometry. The aim was to study the effects of mammalian tachykinins and 5 hydroxytryptamine(5-HT, serotonin) on small bowel motility, with special regard to the migrating motilitycomplex (MMC), contractile force, and transit of small bowel contents. In rats, the natural tachykinins substance P, neurokinin B, neuropeptide K, neuropeptidey and neurokinin A, interrupted the migrating myoelectric complex and induced phaseII-like irregular myoelectric activity. The effect is mediated by all three subsetsof NK receptors but the insensitivity to cholinergic blockade indicates a major rolefor neurokinin-2 receptors directly on smooth muscle cells. In rats, neurokinin Aand neurokinin B also accelerated transit of small bowel contents. In humans, neurokininA interrupted the migrating motor complex, induced phase II-like activity, and increasedthe contraction frequency and amplitude of phase II-like contractions. 5-hydroxytryptamine dose-dependently stimulated the initiation of phase m of themigrating motor complex in rats as well as in humans. In rats, this effect was mediatedmainly by 5-HT3- receptors which are dependent on cholinergic pathways. Thus, in the regulation of the migrating motor complex, the tachykinins stimulatephase II contractions, while 5-HT acts as an initiator of phase III. It can be speculatedthat the major importance of tachykinins in the regulation of small bowel motilityis to enhance contractile activity, while 5-hydroxytryptamine exerts its major influenceon the rhythm of the migrating motor complex. Keywords: Small intestinal motility, MMC, human, rat, tachykinins, serotonin,5 hydroxytryptamine, substance P, neurokinin A. Stockholm 1997 ISBN 91-628-2771-

Dental caries, prevalence and risk factors in patients with Crohn's disease.

OBJECTIVE: The present study tested the hypothesis that patients with Crohn's disease (CD) have a higher prevalence and risk for caries compared to people without CD. MATERIAL AND METHODS: Patients with CD were divided into groups; 71 patients (50.7 ± 13.9 years) who had gone through resective intestinal surgery and 79 patients (42.0 ± 14.4 years) who had not. The patients were compared to 75 controls (48.6 ± 13.4 years) regarding DMF-T and DMF-S, Lactobacilli (LB), Streptococcus mutans (SM), salivary flow and dental plaque. Statistical methods including ANOVA or Chi-square test for calculation of demographic differences between groups, analysis of covariance (ANCOVA) to compare the clinical variable and Post hoc analyses were done with Fischers Least Significant Difference test or Chi-square. Non-parametric Spearman's correlation matrix coefficient was estimated between clinical variables and disease duration. RESULTS: CD patients who had been subjected to resective surgery had a higher DMF-S score (50.7 versus 36.5; p = 0.01) compared to the control group after adjusting for age, gender and smoking. These patients had higher counts of SM (1.5 versus 0.9; p = 0.04) and LB (10000.0 versus 1000.0; p = 0.01), and more dental plaque (53.7 versus 22.6; p = 0.001). CD patients reported a more frequent consumption of sweetened drinks between meals compared to controls (p = 0.001). CONCLUSIONS: The present study shows that patients with CD who had undergone resective surgery had a higher DMFs score, and higher salivary counts of Lactobacilli and Streptococcus mutans compared to the control group

Mediation of irregular spiking activity by multiple neurokinin-receptors in the small intestine of the rat

1. We have studied the small intestinal myoelectric response to the natural tachykinins substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and the neurokinin-receptor selective agonists substance P methyl esther (SPME), [β-Ala(8)]neurokinin A 4-10, and senktide in conscious rats. 2. The effects of the agonists were studied before and after administration of the selective neurokinin (2) (NK(2))-receptor antagonist MEN 10,627. 3. Under basal conditions SP, NKA, NKB, as well as the selective NK(1)-receptor agonist SPME, the NK(2)-receptor agonist [β-Ala(8)]NKA 4–10, and the NK(3)-receptor agonist senktide, disrupted the interdigestive rhythm with regularly recycling migrating myoelectric complexes and induced a phase II-like irregular spiking activity. 4. MEN 10,627 given alone did not affect the interdigestive rhythm. 5. MEN 10,627 inhibited the response to [β-Ala(8)]NKA 4–10 but not to SP, SPME, NKA, NKB or senktide. 6. It is concluded that not only NK(2) receptors, but also other receptors, such as NK(1) and NK(3) receptors, may mediate the motility-stimulating action of different tachykinins in vivo. 7. It is further concluded that MEN 10,627 exerts a selective NK(2)-receptor antagonism, and may be a valuable tool for assessing the functional role of NK(2)-receptors in gastrointestinal physiology

A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine

1. MEN 11420 (nepadutant) is a potent, selective and competitive antagonist of tachykinin NK2 receptors. 2. The objective of the present study was to assess the capability of the drug to antagonize the stimulatory effects of neurokinin A (NKA) on gastrointestinal motility, as well as to change the fasting migrating motor complex (MMC). 3. Thirty-four male volunteers were randomized to treatment with either placebo or MEN 11420 in a double-blinded manner. Effects of MEN 11420 (8 mg intravenously) were evaluated as changes in phases I, II and III of MMC, as well as contraction frequency, amplitude and motility index during baseline conditions and during stimulation of motility using NKA (25 pmol kg(−1) min(−1) intravenously). 4. NKA preceded by placebo increased the fraction of time occupied by phase II, increased contraction frequency, amplitude and motility index. 5. MEN 11420 effectively antagonized the motility-stimulating effects of NKA. MEN 11420 reduced the phase II-stimulating effect of NKA. In addition, the stimulatory effect of NKA on contraction frequency and amplitude, as well as motility index were inhibited by MEN 11420. MEN 11420 did not affect the characteristics of MMC during saline infusion. 6. Plasma levels of MEN 11420 peaked during the first hour after infusion and decreased to less than half during the first 2 h. 7. In conclusion, intravenous MEN 11420 effectively inhibited NKA-stimulated, but not basal gastrointestinal motility, and was well tolerated by all subjects

Demographic data, mean (SD) and percentages (number) for the CD patients (who had not and had undergone resective surgery) and the controls.

<p><i>p</i> 1 indicates significance of the difference between controls and CD patients who had not undergone rescective surgery.</p><p><i>p 2</i> indicates significance of the difference between controls and CD patients who had undergone rescective surgery.</p><p><i>p 3</i> indicates significance of the difference between the 3 groups.</p><p>Significances were calculated with ANOVA and Chi-square test. Post doc analyses were done with Fischers’ least significant difference test. NS = Not significant.</p><p>The difference in CD duration calculated with unpaired Student’s t-test.</p