Colonic Spike Burst Frequency Research Articles

Sex differences in long-term stress-induced colonic, behavioural and hormonal disturbances

Functional bowel disorders are more prevalent in women than in men, but the reason for this is unclear. Stressful experiences can increase the risk for or precipitate intestinal dysfunction. Using a model for long-term stress-induced sensitisation in rats, it was investigated whether male and female rats differ in susceptibility for long-term colonic, behavioural and hormonal disturbances following brief but intense stress. Male and female Wistar rats were fitted with chronic electrodes on proximal colon and given either a 15-minute session of foot shocks or no shocks. Two weeks later, rats were exposed to two different novel stressful challenges in the home cage: an electrified prod (day 14) and an 85 dB noise Stressor (day 15). Digitalised colonic myoelectric spike burst activity was quantified automatically. Behaviour during prod and noise exposure was scored blindly from videotape. Resting plasma hormone concentrations at the end of the study were determined by radio-immuno assay. Following prod stress on day 14, both male and female preshocked rats showed a greater increase in colonic spike burst frequency than controls, but similar behaviour, and the dynamics of colonic motility differed between sexes. Following noise stress on day 15, only a small change in burst frequency was seen in all rats, but preshocked rats showed less self-grooming behaviour and there was a tendency for preshocked females to show increased noise-induced immobility. Preshocked rats also had lower levels of plasma free thyroxine. While both male and female rats show long-term stress-induced colonic sensitisation and hormonal changes, females show a different activation pattern of colonic motility, and may be more vulnerable for altered behavioural reactivity, following stress.

Involvement of a CCK-dependent capsaicin-sensitive afferent pathway in the inhibitory effect of pinaverium bromide on the colonic motor response to eating in rats.

The effects of pinaverium bromide on the stimulation of colonic motility induced by meal and cholecystokinin (CCK) were investigated in rats chronically fitted with intraparietal electrodes on the proximal colon and previously treated or not by capsaicin. Pinaverium bromide inhibited in a dose-related manner (2-50 mg/kg, per os) the increase in colonic spike burst frequency induced by a 3 g meal or CCK-8 (2 micrograms/kg, i.v.). The CCK-A and CCK-B antagonists, devazepide and L 365260 (100 micrograms/kg, i.p.), respectively, inhibited the postprandial colonic motor response while only L 365260 reduced the CCK-induced stimulation. The effects of pinaverium bromide and CCK antagonists were not observed in capsaicin-treated animals. Moreover, CCK-8 (2 micrograms/kg, i.v.) did not stimulate colonic motility after capsaicin treatment. The inhibition of postprandial colonic motility by pinaverium bromide, given orally at therapeutic doses, involves a CCK-dependent pathway which requires the integrity of capsaicin-sensitive afferents.

Sensitization of the colonic response to novel stress after previous stressful experience.

Stressful life events may be important causative or precipitating factors for functional gastrointestinal disorders such as the irritable bowel syndrome in humans. In the rat, a single session of foot shocks is known to sensitize the behavioral and hormonal responses to subsequent stress, but intestinal responses have not been investigated. Rats were fitted with bipolar electrodes on proximal colon and exposed to a single session of foot shocks (10 x 6 s in 15 min; preshocked) or no shocks (control). Weight gain after foot shocks was identical to that in controls. Two weeks after foot shocks, basal colonic spike burst frequency did not differ from controls or from that recorded before shock treatment. Unlike controls, however, preshocked rats showed a significant increase in colonic spike burst frequency to a novel stressful challenge in the home cage, an electrified prod. Because the behavioral responses to this challenge did not differ, colonic hyperresponsiveness in preshocked rats may represent a form of stress-induced autonomic sensitization. The model should be a useful tool to study mechanisms and pharmacotherapeutic approaches of the gastrointestinal consequences of traumatic stress.

Effects of novelty and conditioned fear on small intestinal and colonic motility and behaviour in the rat

Novelty and conditioned fear were used to investigate the effects of psychological stress on fasting small intestinal and colonic myoelectric activity and their relation with behaviour in freely moving rats fitted with bipolar electrodes on proximal jejunum and colon. Rats in both novelty and conditioned fear groups spent a 15 min session in a novel box, where only rats in the fear group received unescapable, repeated foot shock (10 × 6 s, 0.5 mA). Behaviour in groups reexposed to the box on day 1 or day 7 indicated a profound difference in emotional state. Conditioned fear rats remained largely immobile, while novelty rats displayed active exploratory behaviour. Behaviour during conditioned fear did not differ significantly between rats reexposed to the box either 1 or 7 days after foot shock, while novelty animals appeared more aroused on day 7. Conditioned fear on day 1 caused a significant increase in colonic spike burst frequency compared to basal values in the home cage. A smaller but significant increase was found in novelty rats. In groups tested after 7 days, both novelty and conditioned fear resulted in small increases in colonic burst frequency that did not differ significantly from each other. No effects were found on the incidence of the fasting jejunal Migrating Motility Complex. Defecation was see only in conditioned fear rats, but did not differ quantitatively between day 1 and day 7. We conclude that, in the rat, colonic myoelectric spike burst activity is highly responsive to psychological stress, while the fasting pattern of small intestinal activity is more resistant. The behavioural data indicate that the colonic response to stress is determined by the gross emotional impact of the stressor, but may show adaptation at longer intervals after shock conditioning.

Further evidence on the role of central cholecystokinin-B (CCK-B) receptors in anxiety: A study with GV 1500013 a novel CCK-B antagonist

Intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) and emotional stress (ES) induce stimulation of colonic motility in rats, an effect blocked by i.c.v. injection of CCK-8s. This study examined in rats the contribution of the central nucleus of the amygdala (CA) in the blocking effect of CCK-8s on ES and CRF-induced colonic hypermotility. CRF (500 ng/kg, i.c.v.) induced a 73.5% increase in colonic spike burst frequency. Bilateral infusions of 1, 5, 10 and 20 ng/kg of CCK-8s in the CA region 10 min prior to CRF i.c.v. injection reduced, in a dose related manner, the CRF-induced stimulation of colonic motility. A 109% increase in colonic spike burst frequency was observed in rats placed in a test cage in which they had previously received electric footshocks (ES). CCK-8s and A-71623, a selective CCK-A receptor agonist, (10, 25 and 50 ng/kg) infused bilaterally into the CA, 30 min before ES, significantly reduced this stimulatory effect, while CCK-4 and A-63387, a selective CCK-B receptor agonist (10, 25 and 50 ng/kg), had no effect on such a response. CA lesions by ibotenic acid did not affect ES-induced increase in colonic spike activity. However, CCK-8s (50 ng/kg) microinfused into CA lesioned rats was unable to block the ES-induced stimulation of colonic motility, while CCK-8s i.c.v. injected (100 ng/kg) is still active on the colonic response to ES. These results suggest that CA is a site of interaction of CCK-8s with CRF to block the colonic response to stress and that these effects involve the CCK-A receptor subtype. Furthermore, CA is not a brain structure involved in stress-induced stimulation of colonic motility.

Induction of postprandial intestinal motility and release of cholecystokinin by polyamines in rats.

Polyamines are known to play a major role in postprandial adaptation of the digestive tract. Experiments were designed to determine whether ingested polyamines induce change in intestinal motility associated with a cholecystokinin (CCK) release and whether endogenous polyamines are involved in the intestinal and colonic motor response to a meal. Intestinal and colonic motility was assessed in rats equipped with intestinal electrodes, and plasma CCK was determined using a bioassay. Orogastric administration of putrescine, spermidine, or spermine (20 mumol) disrupted intestinal migrating myoelectric complexes (MMCs) and increased the frequency of colonic spike bursts. After a 6-day treatment with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine, the duration of postprandial disruption of MMCs, but not the stimulation of colonic motility, induced by a 3-g meal was significantly reduced. The duration of MMC disruption and the increase in colonic spike burst frequency after spermidine administration (20 mumol) were significantly reduced by CCK-A and CCK-B antagonists. Eight minutes after saline administration plasma CCK concentration was 0.9 +/- 0.4 pM; it rose to 4.7 +/- 2.8 pM, 8 min after spermidine (20 mumol). These results indicate that exogenous polyamines disrupt intestinal MMCs and stimulate colonic motility through a release of CCK acting at CCK-A and CCK-B receptors and suggest that endogenous polyamines are involved in the postprandial control of intestinal motility.

Cholecystokinin blockade of emotional stress- and CRF-induced colonic motor alterations in rats: role of the amygdala

Intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) and emotional stress (ES) induce stimulation of colonic motility in rats, an effect blocked by i.c.v. injection of CCK-8s. This study examined in rats the contribution of the central nucleus of the amygdala (CA) in the blocking effect of CCK-8s on ES and CRF-induced colonic hypermotility. CRF (500 ng/kg, i.c.v.) induced a 73.5% increase in colonic spike burst frequency. Bilateral infusions of 1, 5, 10 and 20 ng/kg of CCK-8s in the CA region 10 min prior to CRF i.c.v. injection reduced, in a dose related manner, the CRF-induced stimulation of colonic motility. A 109% increase in colonic spike burst frequency was observed in rats placed in a test cage in which they had previously received electric footshocks (ES). CCK-8s and A-71623, a selective CCK-A receptor agonist, (10, 25 and 50 ng/kg) infused bilaterally into the CA, 30 min before ES, significantly reduced this stimulatory effect, while CCK-4 and A-63387, a selective CCK-B receptor agonist (10, 25 and 50 ng/kg), had no effect on such a response. CA lesions by ibotenic acid did not affect ES-induced increase in colonic spike activity. However, CCK-8s (50 ng/kg) microinfused into CA lesioned rats was unable to block the ES-induced stimulation of colonic motility, while CCK-8s i.c.v. injected (100 ng/kg) is still active on the colonic response to ES. These results suggest that CA is a site of interaction of CCK-8s with CRF to block the colonic response to stress and that these effects involve the CCK-A receptor subtype. Furthermore, CA is not a brain structure involved in stress-induced stimulation of colonic motility.

Reversal of CRF- and dopamine-induced stimulation of colonic motility by CCK and igmesine (JO 1784) in the rat.

1. The role of dopamine in the genesis of corticotropin releasing factor (CRF)- and emotional stress (ES)-induced stimulation of colonic motility, as well as the mechanism of antagonistic action of cholecystokinin octapeptide (CCK-8s) and igmesine (alpha sigma receptor ligand, formerly JO 1784) on dopamine-induced colonic hypermotility, have been investigated in the rat. 2. ES and i.c.v. injection of CRF (0.5 microgram kg-1) increased the frequency of colonic spike bursts by 63% and 114%, respectively. Prior i.c.v. administration of (+)-SCH 23390 (a D1 receptor antagonist, 10 micrograms kg-1) significantly (P < 0.05) reduced the CRF- and ES-induced increase in colonic spike burst; whereas, sulpiride (a D2 receptor antagonist, 10 micrograms kg-1) blocked the CRF-induced stimulation of colonic spike bursts but had no effect on the colonic response to stress. 3. I.c.v. injection of dopamine (100 micrograms kg-1), increased colonic spike burst frequency by 54%. (+)-SKF 38393 (5 micrograms kg-1), a selective D1 receptor agonist, and quinpirole (5 micrograms kg-1), a selective D2 receptor agonist, increased colonic spike burst frequency by 71% and 70% respectively. CCK-8s (0.1 microgram kg-1) and igmesine (0.1 microgram kg-1) injected i.c.v. completely prevented the stimulatory effects of dopamine, (+)-SKF 38393 and quinpirole. 4. Previous i.c.v. injection of devazepide, a CCKA receptor antagonist, (10 micrograms kg-1) antagonized the inhibitory effects of both CCK-8s and igmesine injected i.c.v. on dopamine-induced colonic hyperkinesia. 5. These results show that CRF stimulates colonic motility through activation of central dopaminergic mechanisms in response to stress; furthermore, CCK-8s inhibits dopamine-induced colonic hyperkinesia through a mechanism involving D1 and D2 receptors. The sigma receptor ligand igmesine, blocks the CRF and ES-induced colonic hyperactivity via an interaction with central CCK mechanisms.

Comparative involvement of 5-HT 1, 5-H 2 and 5-HT 3 receptors in stress-induced colonic motor alterations in rats

The role of 5-HT 1, 5-HT 2 and 5-HT 3 receptors in the genesis of colonic motor alterations induced by emotional stress was evaluated in rats equipped with implanted nickel/chrome electrodes on the proximal colon and a catheter into the lateral ventricle of the brain. In control rats the frequency of colonic spike bursts increased from 7.6 ± 1.3 to 16.8 ± 1.3 per 10 min when the rats were placed in a test cage in which they had previously received electric footshocks. I.p. injection of methysergide (0.1 mg/kg) reduced by 54% the emotional stress-induced increase of colonic spike burst frequency, while a higher dosage (1 mg/kg) of methysergide had no effect. The i.p. injection of ketanserin (a 5-HT 2 receptor antagonist, 0.1 and 1 mg/kg) or granisetron (a 5-HT 3 receptor antagonist, 0.1 and 1 mg/kg) had no effect on emotional stress-induced colonic hyperkinesia. The i.p. injection of the 5-HT 1A receptor agonists, buspirone (1 mg/kg) or 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) (0.05 and 0.1 mg/kg) or benzodiazepine (clonazepam, 1 mg/kg) significantly reduced or suppressed the emotional stress-induced increase of colonic spike bursts. Injected i.c.v., buspirone, but not 8-OH-DPAT, also reduced the emotional stress-induced hyperkinesia. Pretreatment with devazepide receptor (1 μg/kg) antagonized the inhibitory effects of buspirone and 8-OH-DPAT injected i.p. on emotional stress-induced colonic hyperkinesia but did not alter the effects of clonazepam (1 mg/kg). These results suggest that, in rats, (i) 5-HT 1 but not 5-HT 2 and 5-HT 3 receptors are involved in the mediation of emotional stress-induced stimulation of colonic motility and (ii) 5-HT 1A receptor agonists inhibit stress-induced colonic disturbances by activating central cholecystokinin neurons through an afferent pathway from a peripheral site of action.

Involvement of central dopamine and D1 receptors in stress-induced colonie motor alterations in rats

The role of central versus peripheral influence of dopamine (DA) in the genesis of emotional stress (ES) induced by fear to receive electric footshocks on colonic motility was evaluated in rats equipped with implanted electrodes on the proximal colon. In control rats, the frequency of colonic spike bursts increased from 7.5 ± 1.9 to 16.0 ± 2.1 per 10 min when the rats were placed in a test box where they had previously received electric footshocks. This increase induced by ES was significantly p < 0.05, reduced by previous ICV or IP administration of (+)SCH 23390 (a D1receptor antagonist) at doses of 10 and 100 μg/Kg, respectively. Although sulpiride (a D2 antagonist) injected ICV or IP at similar doses had no effect on the ES-induced increase in the frequency of colonic spike bursts. DA (100 μg/kg), and the selective D1 (SKF 38383) or D2 (quinpirole) receptor agonist injected ICV at a dose of 5 μg/kg also increased significantly by 48.7, 54.8, and 68.7%, respectively, the colonie spike burst frequency whereas they are inactive when injected IP at similar and higher doses. These results suggest that, in rats, (a) emotional stress stimulates colonie motility through the stimulation of dopaminergic neurons involving D1 receptors and (b) exogenous activation of central D1 and D2 receptors similarly stimulate colonic motility by increasing the occurrence of colonic spike bursts.

CNS vasopressin mediates emotional stress and CRH-induced colonic motor alterations in rats.

The effects of emotional stress (ES) corresponding to conditioned fear on colonic motility and its antagonism by [deamino-Pen1, Val4, D-Arg8]vasopressin, a vasopressin antagonist, were investigated by electromyography in conscious fasted rats fitted with chronically implanted electrodes. A 117% increase (19.6 +/- 2.1 vs. 9.0 +/- 0.9 cycles/10 min during the control period) in the frequency of colonic spike bursts was observed when rats were placed for 30 min in a box in which they had previously received electric foot shocks. Intracerebroventricular (icv) administration of corticotropin-releasing hormone (CRH; 0.5 micrograms/kg) mimicked the effects of ES and increased the spike burst frequency of the colon by 88.6% from 5 to 15 min after its administration. At doses between 5 and 20 micrograms/kg the antagonist [deamino-Pen1, Val4, D-Arg8]vasopressin significantly reduced or abolished the effects of ES and CRH administration on colonic motility. Injected icv at doses of 2.5 and 5 ng/kg [Arg8]vasopressin dose dependently increased the frequency of colonic spike bursts. These effects were not reproduced by similar or higher (50 ng/kg) doses given intraperitoneally, and the effects were abolished after previous administration of vasopressin at a dose of 20 micrograms/kg. It is concluded that the effects of ES on colonic motility in rats previously shown to be linked to the central nervous system (CNS) release of CRH are in turn mediated through the central release of vasopressin.

Conditioned emotional response in rats enhances colonic motility through the central release of corticotropin-releasing factor

The effect of a mental stress model corresponding to conditioned fear on cecocolonic motility was evaluated electromyographically in intact and hypophy-sectomized rats equipped with electrodes implanted in the cecum and proximal colon over a long period and a small polyethylene catheter inserted into the right lateral ventricle of the brain. Intact fasted and fed rats showed an increase of 82.3% and 67.2%, respectively, in colonic spike-burst frequency when placed for 30 minutes in a box in which they had previously received electrical shocks in their feet. Intracerebroventricular administration of corticotropin-releasing factor (0.5 μg/kg) mimicked the effects of mental stress and increased cecocolonic spikeburst frequency by 75.8%. The specific corticotropin-releasing factor receptor antagonist α-helical CRF9–41 given intracerebroventricularly (5 μ/kg) prevented both the effects of mental stress and corticotropin-releasing factor (0.5 μg/kg intracerebroventricularly) on colonic spike-burst frequency. In contrast, diazepam (0.5 mg/kg IM) suppressed colonic hypermotility induced by mental stress but not that resulting from intracerebroventricular injection of corticotropin-releasing factor (0.5 (μg/kg). Increased colonic spike-burst frequency induced either by stress or by central administration of corticotropin-releasing factor was not prevented by hypophysectomy. It was concluded that mental stress increases the frequency of cecocolonic spike-burst activity and that these effects are related to the central release of corticotropin-releasing factor because they are blocked by a corticotropin-releasing factor antagonist and reproduced by intracerebroventricular administration of corticotropin-releasing factor. Moreover, mental stress-induced colonic motor alterations are mediated by the autonomic nervous system rather than by the hypothalamopituitary axis because they are not abolished by hypophysectomy.

The effect of Strongylus vulgaris larvae on equine intestinal myoelectrical activity

The myoelectrical activity of the ileum, caecum and large colon was monitored from Ag-AgCl bipolar recording electrodes in four conscious 'parasite-naive' weanling foals. All foals were inoculated with 1000 infective 3rd-stage Strongylus vulgaris larvae and alterations to the myoelectrical activity observed. The frequencies of caecal and colonic spike bursts increased significantly in all post infection periods coinciding with assumed larval penetration into the intestinal mucosa and migration through the vasculature. Peaks in caecal and colonic activity occurred at Days 1 to 5 post infection. In the caecum, peaks occurred again at Days 15 and 31 post infection, preceding similar rises in colonic spike burst frequency at Days 19 and 35. Longer term changes indicated a return towards pre-infection levels of activity suggesting smooth muscle adaptation to decreased blood flow. The analysis of caecal and colonic spike burst propagation indicated that the increases in burst frequency were not attributable to an increase in the propagation of spike bursts in any particular direction, but rather to proportional increases in all directions of activity. There was a slight decrease in the simple ileal spike burst frequency immediately post-infection. None of the experimental animals exhibited signs of abdominal pain during the trial, and there was no evidence of bowel infarction at post mortem examination despite the presence of severe parasite-induced arterial lesions. The results suggest that increased caecal and colonic motility is an important host response in susceptible foals exposed to S. vulgaris larvae.