Effect and mechanism of acupuncture on gastrointestinal diseases.

Acupuncture modulates various biomechanical responses, such as prokinetic, antiemetic, and antinociceptive effects. Acupuncture treatment involves the insertion of thin needles into the skin and underlying muscle and the needles are stimulated manually or electrically. Thus, acupuncture stimulates the somatic afferent nerves of the skin and muscles. The somatic sensory information from the body is carried to the cortex area of the brain. Somatic sensory fibers also project to the various nuclei, including the brain stem, periaqueductal gray (PAG), and paraventricular nucleus (PVN) of the hypothalamus. Somatosensory pathways stimulated by acupuncture activate these nuclei. Activation of the brain stem modulates the imbalance between sympathetic activity and parasympathetic activity. Opioid released from the PAG is involved in mediating antiemetic and antinociceptive effects of acupuncture. Oxytocin release from the PVN mediates antistress and antinociceptive effects of acupuncture. Acupuncture may be effective in patients with functional gastrointestinal (GI) disorders because of its effects on GI motility and visceral pain. It is expected that acupuncture is used in the treatment of patients with functional GI disorders.

Impaired adaptation of gastrointestinal motility following chronic stress in maternally separated rats.

Exposure to early life stress causes increased stress responsiveness and permanent changes in the central nervous system. We recently showed that delayed gastric emptying (GE) and accelerated colonic transit (CT) in response to acute restraint stress (ARS) were completely restored following chronic homotypic stress (CHS) in rats via upregulation of hypothalamic oxytocin (OXT) expression. However, it is unknown whether early life stress affects hypothalamic OXT circuits and gastrointestinal motor function. Neonatal rats were subjected to maternal separation (MS) for 180 min/day for 2 wk. Anxiety-like behaviors were evaluated by the elevated-plus-maze test. GE and CT were measured under nonstressed (NS), ARS, and CHS conditions. Expression of corticotropin-releasing factor (CRF) and OXT in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real time RT-PCR and immunohistochemistry. MS increased anxiety-like behaviors. ARS delayed GE and accelerated CT in control and MS rats. After CHS, delayed GE and accelerated CT were restored in control, but not MS, rats. CRF mRNA expression was significantly increased in response to ARS in control and MS rats. Increased CRF mRNA expression was still observed following CHS in MS, but not control, rats. In response to CHS, OXT mRNA expression was significantly increased in control, but not MS, rats. The number of OXT-immunoreactive cells was increased following CHS in the magnocellular part of the PVN in control, but not MS, rats. MS impairs the adaptation response of gastrointestinal motility following CHS. The mechanism of the impaired adaptation involves downregulation of OXT and upregulation of CRF in the hypothalamus in MS rats.

Anti-stress effects of transcutaneous electrical nerve stimulation (TENS) on colonic motility in rats.

BACKGROUND: Disorders of colonic motility may contribute to symptoms in patients with irritable bowel syndrome (IBS), and stress is widely believed to play a major role in developing IBS. Stress increases corticotropin releasing factor (CRF) of the hypothalamus, resulting in acceleration of colonic transit in rodents. In contrast, hypothalamic oxytocin (OXT) has an anti-stress effect via inhibiting CRF expression and hypothalamic-pituitary-adrenal axis activity. Although transcutaneous electrical nerve stimulation (TENS) and acupuncture have been shown to have anti-stress effects, the mechanism of the beneficial effects remains unknown. AIMS: We tested the hypothesis that TENS upregulates hypothalamic OXT expression resulting in reduced CRF expression and restoration of colonic dysmotility in response to chronic stress. METHODS: Male SD rats received different types of stressors for seven consecutive days (chronic heterotypic stress). TENS was applied to the bilateral hind limbs every other day before stress loading. Another group of rats did not receive TENS treatment. RESULTS: TENS significantly attenuated accelerated colonic transit induced by chronic heterotypic stress, which was antagonized by a central injection of an OXT antagonist. Immunohistochemical study showed that TENS increased OXT expression and decreased CRF expression at the paraventricular nucleus (PVN) following chronic heterotypic stress. CONCLUSIONS: It is suggested that TENS upregulates hypothalamic OXT expression which acts as an anti-stressor agent and mediates restored colonic dysmotility following chronic stress. TENS may be useful to treat gastrointestinal symptoms associated with stress.

Hypothalamic circuit regulating colonic transit following chronic stress in rats.

Although acute stress accelerates colonic transit, the effect of chronic stress on colonic transit remains unclear. In this study, rats received repeated restraint stress (chronic homotypic stress) or various types of stress (chronic heterotypic stress) for 5 and 7 days, respectively. Vehicle saline, oxytocin (OXT), OXT receptor antagonist or corticotropin-releasing factor (CRF) receptor antagonists were administered by intracerebroventricular (ICV) injection prior to restraint stress for 90 min. Immediately after the stress exposure, the entire colon was removed and the geometric center (GC) of Na51CrO4 (a nonabsorbable radioactive marker; 0.5 µCi) distribution was calculated to measure the transit. Gene expression of OXT and CRF in the paraventricular nucleus (PVN) was evaluated by in situ hybridization. Accelerated colonic transit with the acute stressor was no longer observed following chronic homotypic stress. This restored colonic transit was reversed by ICV injection of an OXT antagonist. In contrast, chronic heterotypic stress significantly accelerated colonic transit, which was attenuated by ICV injection of OXT and by a CRF receptor 1 antagonist. OXT mRNA expression in the PVN was significantly increased following chronic homotypic stress, but not chronic heterotypic stress. However, CRF mRNA expression in the PVN was significantly increased following acute and chronic heterotypic stress, but not chronic homotypic stress. These results indicate that central OXT and CRF play a pivotal role in mediating the colonic dysmotility following chronic stress in rats.

Mechanism of acupuncture on neuromodulation in the gut--a review.

INTRODUCTION: Acupuncture has been used for treating various gastrointestinal (GI) diseases. However, the mechanism of acupuncture remains unclear. METHODS: The aim of this article is to review the published literature on the mechanism of acupuncture on neuromodulation in the gut. RESULTS: Acupuncture treatment involves the insertion of thin needles into the skin and underlying muscle and the subsequent stimulation of the needles manually or electrically. Thus, acupuncture stimulates the somatic afferent nerves of the skin and muscles. The somatic sensory information from the body is carried to the cortex area of the brain. Somatic sensory fibers also project to the various nuclei at the brain stem and hypothalamus. Via somato-autonomic reflex, acupuncture modulates various biomechanical responses, such as prokinetic, antiemetic, and anti-nociceptive effects. CONCLUSION: According to traditional Chinese medicine, "Acupuncture is believed to restore the balance of Yin and Yang." This can be translated into the Western medicine terminology that "Acupuncture modulates the imbalance between the parasympathetic and sympathetic activity." Acupuncture may be effective in patients with functional GI disorders because of its effects on GI motility and visceral pain.

Sustained acceleration of colonic transit following chronic homotypic stress in oxytocin knockout mice.

Acute restraint stress delays gastric emptying and accelerates colonic transit via central corticotropin releasing factor (CRF) in rats. In contrast, central oxytocin has anxiolytic effects and attenuates the hypothalamus-pituitary-adrenal (HPA) axis in response to stress. Our recent study showed that up regulated oxytocin expression attenuates hypothalamic CRF expression and restores impaired gastric motility following chronic homotypic stress in mice. We studied the effects of acute and chronic homotypic stress on colonic transit and hypothalamic CRF mRNA expression in wild type (WT) and oxytocin knockout (OXT-KO) mice. Colonic transit was measured following acute restraint stress or chronic homotypic stress (repeated restraint stress for 5 consecutive days). (51)Cr was injected via a catheter into the proximal colon. Ninety minutes after restraint stress loading, the entire colon was removed. The geometric center (GC) was calculated to evaluate colonic transit. Expression of CRF mRNA in the supraoptic nucleus (SON) was measured by real time RT-PCR. Colonic transit was significantly accelerated following acute stress in WT (GC=8.1±0.8; n=7) and OXT KO mice (GC=9.4±0.3; n=7). The accelerated colonic transit was significantly attenuated in WT mice (GC=6.6±0.5; n=9) following chronic homotypic stress while it was still accelerated in OXT KO mice (GC=9.3±0.5; n=8). The increase in CRF mRNA expression at the SON was much greater in OXT-KO mice, compared to WT mice following chronic homotypic stress. It is suggested that oxytocin plays a pivotal role in mediating the adaptation mechanism following chronic homotypic stress in mice.

Hypothalamic oxytocin attenuates CRF expression via GABA(A) receptors in rats.

Centrally released oxytocin (OXT) has anxiolytic and anti-stress effects. Delayed gastric emptying (GE) induced by acute restraint stress (ARS) for 90 min is completely restored following 5 consecutive days of chronic homotypic restraint stress (CHS), via up-regulating hypothalamic OXT expression in rats. However, the mechanism behind the restoration of delayed GE following CHS remains unclear. Gamma-aminobutyric acid (GABA)-projecting neurons in the paraventricular nucleus (PVN) have been shown to inhibit corticotropin releasing factor (CRF) synthesis via GABA(A) receptors. We hypothesized that GABA(A) receptors are involved in mediating the inhibitory effect of OXT on CRF expression in the PVN, which in turn restores delayed GE following CHS. OXT (0.5 µg) and selective GABA(A) receptor antagonist, bicuculline methiodide (BMI) (100 ng), were administered intracerebroventricularly (icv). Solid GE was measured under non-stressed (NS), ARS and CHS conditions. Expression of CRF mRNA in the PVN was evaluated by real time RT-PCR. Neither OXT nor BMI changed GE and CRF mRNA expression under NS conditions. Delayed GE and increased CRF mRNA expression induced by ARS were restored by icv-injection of OXT. The effects of OXT on delayed GE and increased CRF mRNA expression in ARS were abolished by icv-injection of BMI. Following CHS, delayed GE was completely restored in saline (icv)-injected rats, whereas daily injection of BMI (icv) attenuated the restoration of delayed GE. Daily injection of BMI (icv) significantly increased CRF mRNA expression following CHS. It is suggested that central OXT inhibits ARS-induced CRF mRNA expression via GABA(A) receptors in the PVN. GABAergic system is also involved in OXT-mediated adaptation response of delayed GE under CHS conditions.

Hypothalamic oxytocin mediates adaptation mechanism against chronic stress in rats.

Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. Although central oxytocin has antistress effects, the role of central oxytocin in stress-induced gastric dysmotility remains unknown. Solid gastric emptying was measured in rats receiving acute restraint stress, 5 consecutive days of repeated restraint stress (chronic homotypic stress), and 7 consecutive days of varying types of stress (chronic heterotypic stress). Oxytocin and oxytocin receptor antagonist were administered intracerebroventricularly (icv). Expression of corticotropin-releasing factor (CRF) mRNA and oxytocin mRNA in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real-time RT-PCR. The changes of oxytocinergic neurons in the PVN were evaluated by immunohistochemistry. Acute stress delayed gastric emptying, and the delayed gastric emptying was completely restored after 5 consecutive days of chronic homotypic stress. In contrast, delayed gastric emptying persisted following chronic heterotypic stress. The restored gastric emptying following chronic homotypic stress was antagonized by icv injection of an oxytocin antagonist. Icv injection of oxytocin restored delayed gastric emptying induced by chronic heterotypic stress. CRF mRNA expression, which was significantly increased in response to acute stress and chronic heterotypic stress, returned to the basal levels following chronic homotypic stress. In contrast, oxytocin mRNA expression was significantly increased following chronic homotypic stress. The number of oxytocin-immunoreactive cells was increased following chronic homotypic stress at the magnocellular part of the PVN. Icv injection of oxytocin reduced CRF mRNA expression induced by acute stress and chronic heterotypic stress. It is suggested that the adaptation mechanism to chronic stress may involve the upregulation of oxytocin expression in the hypothalamus, which in turn attenuates CRF expression.

Central oxytocin is involved in restoring impaired gastric motility following chronic repeated stress in mice.

Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. The development of gastric symptoms may depend on how humans adapt to the stressful events in their daily lives. Although acute stress delays gastric emptying and alters upper gastrointestinal motility in rodents, the effects of chronic stress on gastric motility and its adaptation mechanism remains unclear. Central oxytocin has been shown to have antistress effects. We studied whether central oxytocin is involved in mediating the adaptation mechanism following chronic repeated stress. Mice were loaded with acute and chronic stress (repeated stress for five consecutive days), and solid gastric emptying and postprandial gastric motility were compared between acute and chronic repeated stress. Expression of oxytocin and CRF mRNA in the hypothalamus was studied following acute and chronic repeated stress. Delayed gastric emptying during acute stress (43.1 +/- 7.8%; n = 6, P < 0.05) was completely restored to normal levels (72.1 +/- 2.4%; n = 6) following chronic repeated stress. Impaired gastric motility induced by acute stress was also restored following chronic repeated stress. Intracerebroventricular injection of oxytocin (0.1 and 0.5 microg) restored the impaired gastric emptying and motility induced by acute stress. The restored gastric emptying and motility following chronic repeated stress were antagonized by intracerebroventricular injection of oxytocin antagonists. Oxytocin mRNA expression in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus was significantly increased following chronic repeated stress. In contrast, increased CRF mRNA expression in the SON and PVN in response to acute stress was significantly reduced following chronic repeated stress. Our study suggests the novel finding that the upregulation of central oxytocin expression is involved in mediating the adaptation mechanism following chronic repeated stress in mice.

Extrinsic surgical denervation ameliorates TNBS-induced colitis in rats.

BACKGROUND/AIMS: Neurogenic inflammation refers to an inflammatory reflex arc by sensory neurons which transmit nocious stimulus centrally and results in both pain perception and intense local inflammatory reaction. Specific neurons, receptors, and their respective neurotransmitters have been studied in numerous organ systems including the gastrointestinal tract. Neurogenic inflammation has been suggested to play a key role in the pathogenesis of inflammatory bowel disease. In this study, we studied the effect of surgical denervation of specific somatosensory neurons in a well-established animal model of colitis. METHODOLOGY: Adult male rats were underwent surgical denervation around the inferior mesenteric artery or sham operation. After ten days trinitrobenzene sulfonic acid (TNBS) or vehicle was administered by enema. Inflammation was assessed by, histological evaluation, macroscopic damage score, myeloperoxidase (MPO) activity, and substance P receptor immunoreactivity (SPRIR). RESULTS: Compared with sham operation with TNBS administration, surgical denervation with TNBS administration suppressed the score in all of the inflammatory indices and had almost no signs of inflammation in histological evaluation. CONCLUSIONS: Surgical denervation has a protective effect on TNBS-induced colitis in rats. Thus, sensory neurons play a key role in the pathogenesis of inflammation in this well-established model of acute colitis.

Electroacupuncture improves imbalance of autonomic function under restraint stress in conscious rats.

Acupuncture may modulate the imbalance of the autonomic nervous system. It is well known that restraint stress delays gastric emptying via inhibiting parasympathetic activity and/or stimulating sympathetic activity in rats. We have previously shown that electroacupuncture (EA) improves delayed gastric emptying induced by restraint stress in rats. To investigate whether the beneficial effect of EA on delayed gastric emptying is associated with its modulatory effects on autonomic nervous activity, we utilized spectral analysis of heart rate variability (HRV). In rats, the power in the low frequency (LF; 0.04-1.0 Hz) and high frequency (HF; 1.0-3 Hz) band of HRV represent sympathetic and parasympathetic activities, respectively. Electrocardiography (ECG)-electrodes were implanted on the subcutaneous tissues of the back. One week after the surgery, ECG was recorded before, during and after the restraint stress loading in a conscious state. EA (10 Hz) was applied at bilateral acupuncture points [ST-36 (lower leg) or BL-21 (back)] during restraint stress loading. In response to restraint stress, heart rate and LF component were increased, suggesting the increased activity of sympathetic tone. EA at ST-36 significantly reduced the elevated heart rate and LF, compared to that of control group. EA at ST-36 also significantly increased HF component after finishing the stress loading. In contrast, EA at BL-21 had no significant effect on the heart rate, LF and HF. It is suggested that EA at ST-36 stimulates parasympathetic activity and inhibits sympathetic activity under the restraint stress in rats.

Effects of electroacupuncture on gastric motility and heart rate variability in conscious rats.

To clarify the mechanism of site-specific effects of acupuncture on gastric motor function, we studied the simultaneous recording of gastric motility and electrocardiogram (ECG) for heart rate variability (HRV) analysis in conscious rats. Gastric motility and ECG were recorded before, during and after electroacupuncture (EA) at ST-36 (hind limb) or ST-25 (abdomen). EA at ST-36 significantly increased gastric motility and decreased the ratio of low frequency (LF)/high frequency (HF) of the HRV analysis. In contrast, EA at ST-25 significantly inhibited gastric motility and increased LF/HF ratio. There was a significant correlation observed between the changes of gastric motility and LF/HF ratio in response to EA. It is suggested that the stimulatory effect of EA at ST-36 on gastric motility is associated with its stimulatory effect on vagal activity. The inhibitory effect of EA at ST-25 on gastric motility is associated with its stimulatory effect on the sympathetic nerve activity.

Anatomical evidence of regional specific effects of acupuncture on gastric motor function in rats.

To obtain the anatomical evidences of possible neural pathways in mediating acupuncture-induced gastric motor responses, we studied c-Fos immunohistochemistry of the brain stem in response to acupuncture in rats. Acupuncture needles were inserted at the bilateral acupoints of ST-36 (lower limb) or ST-25 (abdomen) for 30 min. After acupuncture, the brainstem was removed for c-Fos immunohistochemistry. The total number of c-Fos immunopositive cells was counted in the dorsal motor nucleus of the vagus (DMV), the nucleus tractus solitarius (NTS) and the rostral ventrolateral medulla (RVLM). Acupuncture at ST-36, but not ST-25, significantly increased the number of c-Fos immunopositive cells at the DMV to 6.7 +/- 0.4 cells/section, compared to that of controls (1.7 +/- 0.2 cells/section) (n=5, P<0.05). Acupuncture at ST-25, but not ST-36, significantly increased the number of c-Fos immunopositive cells at the RVLM to 12.6 +/- 0.8 cells/section, compared to that of controls (4.2 +/- 0.7 cells/section) (n=5, P<0.05). Acupuncture at ST-36 also increased the number of c-Fos immunopositive cells at the medio-caudal and caudal NTS. On the other hand, acupuncture at ST-25 increased the number of c-Fos immunopositive cells at the medio-caudal NTS. It is suggested that somatic afferents activated by acupuncture at ST-36 is conveyed to the medio-caudal and caudal NTS and stimulates the DMV neurons. In contrast, somatic afferents activated by acupuncture at ST-25 is conveyed to the medio-caudal NTS and stimulates the RVLM neurons. The RVLM neurons are known as premotor sympatho-excitatory neurons that provide drive to the sympathetic preganglionic neurons in the intermediolateral nucleus of the spinal cord. Thus, acupuncture at ST-36 stimulates gastric motility via vagal efferents, while acupuncture at ST-25 inhibits gastric motility via sympathetic efferents in rats.

Wood creosote prevents CRF-induced motility via 5-HT3 receptors in proximal and 5-HT4 receptors in distal colon in rats.

Wood creosote has been used as an herbal medicine against acute diarrhea caused by food poisoning and has an inhibitory effect on colonic motility and enterotoxin-induced ion secretion. Since no previous studies have examined the effects of wood creosote on stress-induced alteration of colonic motility, we examined the effects on the colonic motility altered by intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF), which is a key mediator in responses to stress. We recorded motor activity in proximal and distal colon of unrestrained conscious rats via two manometory catheters. The frequencies of phase III-like contraction and the % motor indices in both proximal and distal colon were measured. At the same time the number of fecal pellets excreted was counted. I.c.v. injection of CRF increased the motor activity in both proximal and distal colon, and these effects were completely antagonized by i.c.v. injection of a selective CRF type 1 antagonist but not by a CRF type 2 antagonist. Changes in colonic motility induced by CRF were reversed by intravenously administered wood creosote. Intraluminal administration of the 5-HT(3) receptor antagonist granisetron, or the 5-HT(4) receptor antagonist SB 204070 blocked the increase in colonic motility induced by i.c.v. injection of CRF. Wood creosote prevented the increase in colonic motility induced by the 5-HT(3) receptor agonist SR57227A in the proximal colon, while it prevented the increase in colonic motility induced by the 5-HT(4) receptor agonist RS67506 in the distal colon. These results indicate that wood creosote prevents the increase in colonic motility induced by CRF via 5-HT(3) receptors in the proximal colon, and via 5-HT(4) receptors in the distal colon, suggesting that wood creosote might be useful to treat stress-induced diarrhea.

Electroacupuncture elicits dual effects: stimulation of delayed gastric emptying and inhibition of accelerated colonic transit induced by restraint stress in rats.

Acupuncture has been used for treating functional gastrointestinal (GI) disorders. Animal studies have demonstrated that acupuncture antagonized various stress-induced responses. We investigated the effects of electroacupuncture (EA) at ST-36 (Zusanli; lower limb) on stress-induced alteration of GI motor activities. Solid gastric emptying was significantly delayed by restraint stress (29.6+/-2.4%; n=7) compared to that of controls (60.0+/-2.5%; n=8). Delayed gastric emptying was significantly improved by EA at ST-36 (47.2+/-1.8%). Intracisternal (IC) injection of corticotropin releasing factor (CRF; 1 microg) delayed gastric emptying to 25.4+/-3.1%, which was also improved by EA at ST-36, to 53.0+/-7.1% (n=8). The stimulatory effect of EA on stress-induced delayed gastric emptying was abolished by atropine (17.6+/-1.9%) but not by guanethidine (42.2+/-2.3%). Colonic transit was significantly accelerated by restraint stress (GC=7.2+/-0.3; n=8) compared to that of controls (GC=5.2+/-0.2; n=8). Accelerated colonic transit was significantly reduced by EA at ST-36 (GC=4.9+/-0.3). IC injection of CRF accelerated colonic transit (GC=6.9+/-0.2), which was also normalized by EA at ST-36 (GC=4.7+/-0.2). The inhibitory effect of EA on stress-induced acceleration of colonic transit was not affected by guanethidine (GC=4.6+/-0.3). In conclusion, EA at ST-36 showed dual effects: stimulation of stress-induced delayed gastric emptying and inhibition of stress-induced acceleration of colonic transit. The stimulatory effect of EA on stress-induced delayed gastric emptying is mediated via cholinergic pathways. The inhibitory effect of EA on stress-induced acceleration of colonic transit is independent of the sympathetic pathway.

Acupuncture for functional gastrointestinal disorders.

Functional gastrointestinal (GI) symptoms are common in the general population. Especially, motor dysfunction of the GI tract and visceral hypersensitivity are important. Acupuncture has been used to treat GI symptoms in China for thousands of years. It is conceivable that acupuncture may be effective in patients with functional GI disorders because it has been shown to alter acid secretion, GI motility, and visceral pain. Acupuncture at the lower limbs (ST-36) causes muscle contractions via the somatoparasympathetic pathway, while at the upper abdomen (CV-12) it causes muscle relaxation via the somatosympathetic pathway. In some patients with gastroesophageal reflux disease (GERD) and functional dyspepsia (FD), peristalsis and gastric motility are impaired. The stimulatory effects of acupuncture at ST-36 on GI motility may be beneficial to patients with GERD or FD, as well as to those with constipation-predominant irritable bowel syndrome (IBS), who show delayed colonic transit. In contrast, the inhibitory effects of acupuncture at CV-12 on GI motility may be beneficial to patients with diarrhea-predominant IBS, because enhanced colonic motility and accelerated colonic transit are reported in such patients. Acupuncture at CV-12 may inhibit gastric acid secretion via the somatosympathetic pathway. Thus, acupuncture may be beneficial to GERD patients. The antiemetic effects of acupuncture at PC-6 (wrist) may be beneficial to patients with FD, whereas the antinociceptive effects of acupuncture at PC-6 and ST-36 may be beneficial to patients with visceral hypersensitivity. In the future, it is expected that acupuncture will be used in the treatment of patients with functional GI disorders.

Electroacupuncture improves restraint stress-induced delay of gastric emptying via central glutaminergic pathways in conscious rats.

Acupuncture has been used for treating functional gastrointestinal (GI) disorders. Animal studies demonstrated that acupuncture improves various stress-induced physiological responses. We investigated the effects of electroacupuncture (EA) at ST-36 (Zusanli; lower limb) on stress-induced delay of gastric emptying. Solid food gastric emptying in 90 min was significantly delayed by restraint stress (27.3 +/- 2.1%, n = 8), compared to that of controls (64 +/- 2.1%, n = 8). Restraint stress-induced delay of gastric emptying was significantly restored by the intracisternal (IC)-injection of GABA(A) receptor antagonist, bicuculline methiodide (46.5 +/- 3.1%; n = 6) and GABA(B) receptor antagonist, phaclofen (48 +/- 3.3%; n = 6). Delayed gastric emptying induced by restraint stress was significantly improved by EA at ST-36 (49.7 +/- 1.4%). The stimulatory effect of EA on stress-induced delay of gastric emptying was prevented by pretreatment with IC-injection of glutamate receptor antagonist, kynurenic acid (30.1 +/- 2.1%). In conclusion, restraint stress-induced delay of gastric emptying is mediated via central GABA(A) and GABA(B) receptors. EA at ST-36 stimulates glutaminergic neurons in the brainstem resulting in improvement of stress-induced delay of gastric emptying.

The herbal medicine, Dai-Kenchu-to, accelerates delayed gastrointestinal transit after the operation in rats.

BACKGROUND: Post-operative ileus (POI) is a transient bowel dysmotility after operation. We have previously shown that laparotomy alone significantly delayed gastrointestinal (GI) transit, compared to anesthesia alone. The GI transit was further delayed after laparotomy plus intestinal manipulation. Dai-Kenchu-to (DKT), an herbal medicine, has been used for treating adhesive bowel obstruction in Japan. We studied whether DKT improves delayed GI transit after the operation, with or without morphine administration in rats. MATERIALS AND METHODS: Under isoflurane anesthesia, POI was induced by laparotomy with intestinal manipulation. Immediately after the operation, the rats received 51Cr by gavage. Three hours after the operation, the rats were sacrificed and GI transit was estimated by calculating the geometric center (GC). DKT (120, 360, and 1,200 mg/kg) were administered by gavage after the operation, with or without morphine administration (1 mg/kg s.c.). A muscarinic receptor antagonist (atropine; 50 mug/kg), a 5HT3 receptor antagonist (ondansetron; 1 mg/kg) and a 5HT4 receptor antagonist (GR113,808; 3 mg/kg) were administered before the operation. Truncal vagotomy was performed preceding the operation. RESULTS: Laparotomy with intestinal manipulation produced a significant delay in GI transit (GC = 2.93 +/- 0.16), compared to that of anesthesia alone (9.51 +/- 0.45). DKT at the dose of 360 mg/kg (GC = 3.77 +/- 0.10, P < 0.01) and 1,200 mg/kg (GC = 3.77 +/- 0.20, P < 0.01) significantly accelerated delayed GI transit induced by operation. Ondansetron, GR113,808, atropine, and truncal vagotomy abolished the stimulatory effect of DKT (360 mg/kg). When morphine was administered, GI transit was further reduced (GC = 1.97 +/- 0.10). DKT at the dose of 360 mg/kg (GC = 2.81 +/- 0.22, P < 0.05) and 1,200 mg/kg (GC = 2.87 +/- 0.23, P < 0.05) significantly improved delayed GI transit in morphine treated rats. CONCLUSIONS: DKT accelerates delayed GI transit induced by intestinal manipulation with and without concomitant morphine administration. DKT treatment may be useful for the patients with POI.