Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention.

BACKGROUND AND AIMS: Determining the gene that plays a key role in brain-gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. METHODS: We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[(15-)O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. RESULTS: Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg to 40 mm Hg than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg compared with 0 mm Hg was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001). CONCLUSION: These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.

Sleep duration and the risk of prostate cancer: the Ohsaki Cohort Study.

In a prospective study of prostate cancer incidence (127 cases), among 22 320 Japanese men, sleep duration was associated with lower risk; the multivariate hazard ratio of men who slept >or=9 h per day compared with those who slept less was 0.48 (95% confidence interval: 0.29-0.79, P for trend=0.02).

Sleep duration and the risk of breast cancer: the Ohsaki Cohort Study.

In a prospective study of 23 995 Japanese women, short sleep duration was associated with higher risk of breast cancer (143 cases), compared with women who slept 7 h per day, the multivariate hazard ratio of those who slept

Determining an optimal dose of linaclotide for use in Japanese patients with irritable bowel syndrome with constipation: A phase II randomized, double-blind, placebo-controlled study.

BACKGROUND: Clinical testing to determine a suitable dose of linaclotide for Japanese patients with irritable bowel syndrome with constipation (IBS-C) was needed. METHODS: This was a randomized, double-blind, placebo-controlled, dose-finding trial. Japanese patients with IBS-C diagnosed using Rome III criteria (n = 559, men/women: 49/510) were randomly assigned to 1 of 4 linaclotide doses (0.0625, 0.125, 0.25, or 0.5 mg) or placebo for the 12-week treatment period. The primary endpoint was responder rate of global assessment of relief of IBS symptoms during 12 weeks. The secondary endpoints included responder rates of complete spontaneous bowel movement (CSBM), SBM and abdominal pain/discomfort relief and others. KEY RESULTS: The primary endpoint was 23.2%, 36.2%, 38.7%, 34.8%, and 38.3% in placebo (n = 112), 0.0625 (n = 116), 0.125 (n = 111), 0.25 (n = 112), and 0.5 (n = 107) mg of linaclotide groups with the difference from the placebo group in each linaclotide group (13.0%, 15.5%, 11.6%, 15.1%, P > .05). Monthly responder rate of global assessment of relief of IBS symptoms at month 3 (48.6%), responder rate of CSBM during 12 weeks (45.8%), and responder rate of abdominal pain/discomfort relief during 12 weeks (32.7%) in the 0.5 mg were significantly higher than those in placebo group (29.5%, P < .01; 25.9%, P < .01; and 18.8%, P < .05 respectively). The most frequent adverse event in the linaclotide groups was diarrhea. CONCLUSIONS & INFERENCES: This study suggests that a linaclotide dose of 0.5 mg may be appropriate in Japanese patients with IBS-C.

Effect of attention bias modification on event-related potentials in patients with irritable bowel syndrome: A preliminary brain function and psycho-behavioral study.

BACKGROUND: Attention bias modification normalizes electroencephalographic abnormalities in alpha and beta power percentages related to attention in patients with irritable bowel syndrome (IBS). Yet, it is unknown whether ABM contributes to the normalization of event-related potentials (ERP) in these patients. We hypothesized that ERP related to attention deficit would be normalized after ABM implementation in individuals with IBS. METHODS: Thirteen patients with IBS and 10 control subjects completed a 2-month intervention that included five ABM sessions. Each session included 128 trials, resulting in a total of 640 trials during the study period. Event-related potentials were measured at the first and fifth sessions. As per the international 10-20 system for electroencephalographic electrode placement, right parietal P4 was evaluated to measure the attention component of facial expression processing. KEY RESULTS: A group comparison of P100 latency at P4 revealed that latencies were significantly different between groups in session 1 (IBS vs control, 108 ± 8 vs 97 ± 14; t = -2.51, P = .0203). This difference was absent in session 5 (94 ± 11 vs 93 ± 11, respectively; t = -0.397, P = .6954, r = .09), indicating an effect of ABM in the IBS group. CONCLUSIONS AND INFERENCES: Attention bias modification may have clinical utility for normalizing brain function and specifically attentional abnormalities in patients with IBS.

Effect of alpha-helical CRH on quantitative electroencephalogram in patients with irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) may have a higher tone of corticotropin-releasing hormone (CRH) in the brain. We tested our hypothesis that peripheral administration of CRH antagonist, alpha-helical CRH(9-41) (alphahCRH), improves decreased alpha power spectra and increased beta power spectra of electroencephalogram (EEG) in IBS patients. A barostat bag was inserted to the descending colon of 10 normal controls and 10 IBS patients. The EEG power spectra and topography were measured during baseline period and colonic distention period with the administration of saline followed by the administration of 10 microg kg(-1) of alphahCRH. IBS patients showed a significantly lower alpha power percentage and a higher beta power percentage than normal controls during baseline. Colonic distention induced a decrease in the alpha power percentage and an increase in the beta power percentage in both groups without difference between groups. After the administration of alphahCRH, changes in the EEG power spectra in response to colonic distention were blunted and the differences in the EEG power spectra between IBS patients and controls vanished. Peripheral administration of alphahCRH almost normalized EEG activities in IBS patients. Our data strongly suggest that CRH plays an important role in IBS.

Role of histaminergic neurons in hypnotic modulation of brain processing of visceral perception.

Modulating visceral sensation of the body is important to the understanding of emotion formation. Molecules that act during hypnosis and modify visceral pain perception are not known. We tested our hypothesis that hypnotic suggestion changes electrophysiological processing of visceroafferent signals in the human brain and that these conditions are in part dependent on histaminergic neurons. Twelve healthy male subjects were studied on two separate days: a day of treatment with histamine H1 receptor antagonist (d-chlorpheniramine 100 microg kg(-1), intravenously) and another day of that with placebo (saline, the same amount) in a randomized order. We recorded cortical evoked potentials to 100 rectal electrical stimuli after neutral, hyperalgesic or analgesic hypnotic suggestions as given to modulate the visceral perception. Analgesic suggestion reduced the amplitude of the deepest positive peak of viscerosensory evoked potential. Administration of histamine H1 antagonist diminished the attenuation of viscerosensory evoked potential by analgesic suggestion. Our results suggest that central pain modulatory system in the brain is activated by hypnotic suggestion and that brain histamine is a mediator in the hypnotic modulation of visceral sensory pathway as well as in the control of consciousness level. These findings lead us to possible new treatment for control of visceral perception.

Optimal dose of ramosetron in female patients with irritable bowel syndrome with diarrhea: A randomized, placebo-controlled phase II study.

BACKGROUND: Previous studies showed that 5 µg of ramosetron, a serotonin (5-hydroxytryptamine: 5-HT)-3 receptor antagonist, is only effective in male patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D). We hypothesized that either dose 1.25, 2.5, or 5 µg of ramosetron would be effective in female patients with IBS-D. METHODS: This randomized, double-blind, placebo-controlled, phase II dose-finding exploratory trial included 409 female outpatients with IBS-D treated in Japan. They were administered oral placebo (n=102), or 1.25 µg (n=104), 2.5 µg (n=104), or 5 µg (n=99) of ramosetron once daily for 12 weeks after a 1-week baseline period. The primary endpoint was monthly responder rates of global improvement of IBS symptoms in the first month. Secondary endpoints included global improvement in the other months, abdominal pain/discomfort, weekly mean changes in the Bristol Stool Form Scale (BSFS), and IBS-QOL. KEY RESULTS: Middle dose (2.5 µg) of ramosetron significantly improved abdominal pain/discomfort at second month (62.5%, P=.002), third month (60.6%, P=.005), and the last evaluation point (63.5%, P=.002) and weekly BSFS (P<.05) except at Week 8, 11, and 12 than placebo. IBS-QOL did not change. Ramosetron induced more constipation than placebo. CONCLUSIONS & INFERENCES: The trial suggested that 2.5 µg of ramosetron is the most effective and least harmful option for treating female patients with IBS-D (Clinicaltrials.gov ID: NCT01274000).

Effect of attention bias modification on brain function and anxiety in patients with irritable bowel syndrome: A preliminary electroencephalogram and psycho-behavioral study.

BACKGROUND: Gastrointestinal symptoms of irritable bowel syndrome (IBS) show a reciprocal relationship with anxiety. In this intervention-based study, we investigated the utility of attention bias modification (ABM) therapy in patients with IBS. We hypothesized that IBS-related electroencephalographic abnormalities would be normalized after ABM therapy. METHODS: Seventeen patients with IBS and 13 healthy subjects completed five ABM intervention sessions over a 2-month period. Each session included 128 ABM trials, resulting in a total of 640 trials across the intervention period. For each trial, subjects viewed a pair of facial expression images and were instructed to indicate the position of the neutral face as quickly and accurately as possible by pressing one of two buttons on a button box. Electroencephalography data (alpha and beta power percentages) were collected during the 1st and 5th sessions. KEY RESULTS: Generalized estimating equations of relative alpha power revealed a significant effect of period was identified at O2 (P=.036). Paired t tests revealed that ABM significantly increased relative alpha power at O2 in patients with IBS. Generalized estimating equation of relative beta power revealed a significant effect of the group × period interaction was identified at Pz (P=.035). Paired t tests revealed that ABM significantly decreased relative beta power at Pz in patients with IBS. CONCLUSIONS & INFERENCES: Attention bias modification may normalize brain function related to attention and anxiety in patients with IBS.

Muscarinic stimulation and antagonism and glucoregulation in nondiabetic and obese hyperglycemic mice.

Plasma glucose and insulin responses to a muscarinic agonist (bethanechol chloride) and a muscarinic antagonist (atropine) were evaluated in obese C57BL/6J ob/ob mice and in lean C57BL/6J + /? mice. In lean +/? mice, plasma glucose decreased in response to 1 and 2 micrograms/g bethanechol chloride, whereas insulin increased significantly. In ob/ob mice, insulin increased remarkably in response to bethanechol administration (saline, 632 +/- 80 microU/ml; 2 micrograms/g bethanechol chloride, 1794 +/- 97 microU/ml; n = 10), but surprisingly, plasma glucose also rose significantly (saline, 230 +/- 14 mg/dl; 2 micrograms/g bethanechol chloride, 363 +/- 18 mg/dl, n = 10). This exaggerated hyperglycemia in ob/ob mice was not associated with significant changes in plasma glucagon. Furthermore, administration of propranolol hydrochloride did not diminish bethanechol chloride-induced hyperglycemia in ob/ob mice. Administration of atropine (2.5, 5, and 10 mg/kg body wt) induced a significant decrease in plasma insulin without changes in plasma glucose in ob/ob mice, whereas neither plasma insulin nor plasma glucose changed in lean mice. Finally, conversion of [14C]alanine to glucose was increased in ob/ob mice after bethanechol chloride administration, indicating that muscarinic stimulation increases gluconeogenesis in an animal model of type II (non-insulin-dependent) diabetes.

Classical conditioned response of rectosigmoid motility and regional cerebral activity in humans.

The relationship between the central processes of classical conditioning and conditioned responses of the gastrointestinal function is incompletely understood in humans. We tested the hypothesis that the rectosigmoid motility becomes conditioned with anticipatory painful somatosensory stimulus and that characteristic brain areas become activated during anticipation. In nine right-handed healthy male subjects, a loud buzzer (CS, conditional stimulus) was paired with painful transcutaneus electrical nerve stimulation to the right hand (unconditional stimulus). Rectosigmoid muscle tone measured by the barostat as the intrabag volume, phasic contractions of the bowel measured as the number of phasic volume events (PVEs), and regional cerebral blood flow assessed by positron emission tomography (PET), were measured before and after conditioning. Following conditional trials, the bag volume after CS alone did not show significant changes between before and after the stimulus, but the number of PVEs after 2-minute interval of the CS alone was significantly greater than that before the stimulus (P < 0.05). The PET data showed the conditioning elicited significant cerebral activation of the prefrontal, anterior cingulate, parietal and insula cortices (P < or = 0.001, uncorrected). Rectosigmoid motility can be conditioned with increase in phasic contractions in humans.

Alcohol consumption and the risk of cancer in Japanese men: the Miyagi cohort study.

The objective of this study was to investigate the association between alcohol consumption and the risk of total cancer, and to estimate the proportion of total cancer attributable to drinking habit in Japanese men. From June through August 1990, a total of 21 201 Japanese men completed a self-administered questionnaire on various health habits, including alcohol consumption. During 153 389 person-years of follow-up through December 1997, we identified a total of 882 cases of cancer. We used Cox proportional hazards regression to estimate the relative risk of total cancer according to categories of alcohol consumption. The risk for total cancer was significantly higher in ex-drinkers than never-drinkers. There was a dose-response relationship between the amount of alcohol consumed and the risk of total cancer among current drinkers: multivariate RRs in reference to never-drinkers (95% confidence intervals (CI)) were 1.1 (0.8-1.3), 1.3 (1.0-1.7), and 1.3 (1.1-1.7) in current drinkers who consumed less than 22.8 g, 22.8-45.5 g, 45.6 g or more alcohol per day, respectively (P for trend <0.001). Estimated 17.9% (95% CI 3.1-30.5) of total cancer risk was attributable to drinking habit. In our findings, approximately 20% of the total cancer cases in Japanese men may be prevented by alcohol control.

Effect of 5-hydroxytryptamine receptor 4 agonist mosapride on human gastric accommodation.

BACKGROUND: Impaired gastric accommodation is one of the major features of functional dyspepsia. Mosapride citrate is a 5-hydroxytryptamine receptor 4 (5-HT4) agonist, which is shown to improve upper abdominal symptoms. However, effect of mosapride on gastric accommodation was not clear. We tested the hypothesis that mosapride enhances the gastric accommodation in normal individuals. METHODS: Fourteen male healthy volunteers completed this study. Single administration of mosapride or placebo was performed randomly with more than 1-week interval. Subjects swallowed a triple-lumen polyvinyl tube with a polyethylene bag. The bag was positioned in the proximal stomach and the minimal distending pressure (MDP) was determined. The ramp distension starting from the MDP was then performed and subjects were instructed to score their perception using ordinate scales. Next the intra-bag pressure was set at MDP + 2 mmHg and a liquid meal was administered 30 min later, and the intra-bag volume was recorded for 60 min. We compared the MDP, perception scores, and the intra-bag volume changes by administering placebo and mosapride. KEY RESULTS: Minimal distending pressure was not significantly different in subjects receiving mosapride or placebo. Treatment with mosapride had no effect on intra-bag pressures or volumes inducing first sensation or discomfort. Gastric accommodation, expressed as the difference between pre- and postmeal intra-bag volumes, and the percent change of the intra-bag volumes by the meal was significantly enhanced by mosapride compared with placebo. CONCLUSIONS & INFERENCES: This is the first study clearly demonstrating that single administration of 5-HT4 agonist can enhance gastric accommodation in humans. (Umin.ac.jp, number UMIN000014063).

Injection of corticotropin-releasing hormone into the amygdala aggravates visceral nociception and induces noradrenaline release in rats.

BACKGROUND: Corticotropin-releasing hormone (CRH) and its receptor 1 (CRH-R1) play an important role in the colonic response to stress. The central nucleus of the amygdala (CeA) is a major extrahypothalamic site that contains a large number of neurons expressing both CRH and CRH-R1. Here, we verified the hypothesis that CRH in the CeA sensitizes visceral nociception via CRH-R1 with release of noradrenaline, dopamine, and serotonin (5-HT) in the CeA. METHODS: In male Wistar rats, visceral sensitivity was quantified by recording the visceromotor response to colorectal distension (CRD) with administration of vehicle, CRH, or the CRH-R1 antagonist CP-154526+ CRH or CRH-R1 antagonist CP-154526 alone into the CeA. Simultaneously, extracellular levels of noradrenaline, dopamine, and 5-HT were measured in the CeA using microdialysis. All data were obtained under restraint conditions. KEY RESULTS: Administration of CRH into the CeA significantly increased the number of abdominal muscle contractions in response to CRD. CP-154526 significantly blocked the number of abdominal muscle contractions in response to CRD with the administration of CRH into the CeA. Noradrenaline in the CeA was increased by CRD, further increased by CRH, and inhibited by CRH-R1 antagonist. Dopamine in the CeA was also exaggerated by CRH but was not inhibited by CRH-R1 antagonist. 5-HT in the CeA was unchanged. CONCLUSIONS & INFERENCES: These results suggest that CRH in the CeA sensitizes visceral nociception via CRH-R1 with release of noradrenaline.

Psychophysiological stress induces heat shock cognate protein 70 messenger RNA in the hippocampus of rats.

Psychophysiological stress has been shown to increase 70,000 mol. wt heat shock protein messenger RNAs with northern blotting in rats. However, its localization is unknown. With in situ hybridization, we tested our hypothesis that restraint water-immersion stress may induce heat shock cognate protein 70 messenger RNA expression simultaneously with some morphological changes selectively in the hippocampus of rats. Stress for 6 h significantly increased heat shock cognate protein 70 messenger RNAs in the hippocampus, with maximal intensity in the CA3 subfield of the Ammon's horn and to a lesser extent in CA2. Stress for 12 h significantly increased heat shock cognate protein 70 messenger RNAs in the whole hemisphere including the cerebral cortex, the thalamus, the hypothalamus, and the hippocampus with the highest density in CA3. Heat shock cognate protein 70 messenger RNA in rats with stress for 6 h followed by recovery for 6 h significantly increased at CA3 and CA2 compared with the controls or rats stressed for 6 h without recovery. No overt histological changes were detected in neuronal or glial cells in the slides of hematoxylin-eosin or Cresyl Violet staining. These results show that psychophysiological stress induces heat shock cognate protein 70 messenger RNA in the most stress-vulnerable brain structure, hippocampal CA3, probably for cytoprotection.

Influence of night shift work on psychologic state and cardiovascular and neuroendocrine responses in healthy nurses.

Night shift work has often been associated with increasing degree and frequency of various psychologic complaints. The study examined whether psychologic states after night work are related to adaptive alterations of the cardiovascular and neuroendocrine systems. We studied 18 healthy nurses (age 29+/-2 years) engaged in a modified rapid shift rotation system (day work, 8:15-17:15; evening work, 16:00-22:00; night work, 21:30-8:30). Blood pressure, heart rate, RR interval variability (L/H and HF power spectrum for sympathetic and vagal activities), and physical activity were measured using a multibiomedical recorder for 24 h from the start of work during the night and day shifts. Plasma ACTH and cortisol concentrations were measured at the end of each shift and at 8:30 AM on a day of rest. Each subject's psychologic state was assessed using a validated questionnaire. Among the parameters measured, scores for confusion, depression, anger-hostility, fatigue and tension-anxiety were highest, and scores for vigor lowest, after a night shift. Systolic blood pressure and heart rate during work were lower during night shift than during day shift (119+/-2 vs. 123+/-1 mmHg, p<0.05 and 75+/-1 vs. 84+/-2 bpm, p<0.001, respectively). Both parameters were lower still (p<0.005 and p<0.05) when measured outside of the hospital under waking conditions following a night shift than following a day shift, even though the levels of physical activity were similar. The HF power spectrum of RR interval variability was greater not only during work (24.2+/-2.1 vs. 18.5+/-1.8 ms, p<0.005) but also during the awake period (29.1+/-2.5 vs. 24.4+/-2.6 ms, p<0.005) after the night shift compared with the day shift. Plasma ACTH and cortisol concentrations were lower after night work than in the day of rest (7.3+/-1.2 vs. 11.5+/-2.3 pg/ml, p<0.1 and 11.1+/-1.1 vs. 14.4+/-1.1 mg/dl, p< 0.05). Systolic and diastolic blood pressures during night shift work and the subsequent awake period correlated positively with scores for vigor and negatively with scores for confusion (p<0.05). Plasma ACTH and cortisol concentrations did not correlate with any psychologic scores. We conclude that psychologic disturbances after night work were associated with altered cardiovascular and endocrine responses in healthy nurses. Some of the psychologic complaints may be attributable to lower waking blood pressure.

Abnormal visceral perception in patients with functional dyspepsia: use of cerebral potentials evoked by electrical stimulation of the oesophagus.

Altered visceral perception is thought to be included in the pathogenesis of functional dyspepsia. However, in previous studies, the assessment of visceral perception has been based solely on patients self-reported symptoms. Cerebral evoked potential (EP), either by mechanical or electrical stimulation (ES) of the visceral organ, is used to evaluate visceral perception via afferent neural pathways. In this study, we investigated the visceral perception in patients with functional dyspepsia by EP to eliminate the possibility of self-reported bias. EP responses were recorded by oesophageal ES at 37 cm from the nostril in 14 patients with functional dyspepsia and 14 normal healthy control subjects. Threshold levels of perception, peak latencies and peak-to-peak amplitudes of EP were evaluated. There was no difference in the sensory threshold between the dyspeptic patients and the control subjects (median 6 mA, range 2-12 mA, vs. 8 mA, range 6-14 mA; P= 0.09). There was a strong trend towards a decreased discomfort threshold in the patients when compared to the control subjects (median 14 mA, range 6-24 mA vs. 20 mA, range 14-26 mA; P = 0.05). The latency of the later EP peak (N2) among the patients (154 ¿ 4 ms) was significantly shorter than that of the control subjects (171 ¿ 3 ms, P < 0.01) although there was no difference between the earlier peaks (Ni and P1). There was also no difference in the amplitudes (Ni/Pi and P1/N2) of EP between the patients and the control subjects. Half of the patients (seven out of 14) complained of nausea during ES but the control subjects were unaffected. The latency of the first EP peak (Ni) in the patients with nausea was significantly shorter (66 ¿ 3 ms) than that of the patients without nausea (79 ¿ 4 ms, P 0.05) or among the control subjects (80 ¿ 3 ms, P < 0.05). These results suggest that dyspeptic patients may recruit a greater number of fast conducting myelinated nerve fibres that convey visceral afferent impulses to the brain and/or that dyspeptic patients may have an altered central processing of the visceral perception. We conclude that EP recording by oesophageal ES provides an objective measurement of altered visceral perception in patients with functional dyspepsia.

Brain activity during distention of the descending colon in humans.

Brain-gut interaction is considered to be a major factor in the pathophysiology of irritable bowel syndrome. However, only limited information has been provided on the influence of gastrointestinal tract stimulation on the brain. Our aim in this study was to determine the specific regions of the brain that are responsible for visceral perception and emotion provoked by distention of the descending colon in humans. Fifteen healthy males aged 22 +/- 1 participated in this study. Using a colonoscope, a balloon was inserted into the descending colon of each subject. After sham stimulation, the colon was randomly stimulated with bag pressures of 20 and 40 mmHg, and regional cerebral blood flow was measured by [(15)O] positron emission tomography. The subjects were asked to report visceral perception and emotion using an ordinate scale of 0-10. Colonic distention pressure dependently induced visceral perception and emotion, which significantly correlated with activation of specific regions of the brain including the prefrontal, anterior cingulate, parietal cortices, insula, pons, and the cerebellum. In conclusion, distention of the descending colon induces visceral perception and emotion. These changes significantly correlate with activation of specific regions in the brain including the limbic system and the association cortex, especially the prefrontal cortex.

Brain-gut induction of heat shock protein (HSP) 70 mRNA by psychophysiological stress in rats.

Restraint water-immersion stress-induced expression of heat shock protein (HSP)70 mRNA in the cerebral cortex and stomach of rats was evaluated by Northern blotting. Cerebral and gastric HSP70 mRNA significantly increased in the 6 h-stressed rats and the amount of mRNA measured as optical densities was highest in the 12 h-stressed rats. These data confirmed our previous observations and suggest that families of HSPs play a salient cytoprotective role in stress-vulnerable organs.

Psychophysiological stress induces heat shock cognate protein (HSC) 70 mRNA in the cerebral cortex and stomach of rats.

Families of 70 kDa heat shock proteins have essential roles in cellular coping to noxious stimuli. However, their roles in psychophysiological stress have not been precisely clarified. We tested our hypothesis that heat shock cognate protein (HSC)70 messenger RNA would increase in stress-vulnerable organs under psychophysiological stress. In control rats, cerebral HSC70 mRNAs were constitutively expressed while gastric HSC70 mRNAs were scarcely identified. Restraint-water immersion stress significantly increased the level of cerebral HSC70 mRNAs for 6 h and 12 h. Stress for 6 h with recovery for 6 h induced more gastric HSC70 mRNA levels than that without recovery, while stress for 12 h expressed the highest gastric HSC70 mRNA levels. Hypothermia, induced by water immersion, excluded a possible role of hyperthermia in inducing HSC70 mRNA. Our results point to a crucial cytoprotective role for families of heat shock proteins in stress-vulnerable brain-gut link in mammals under psychophysiological stress.