Low-level laser therapy for tinnitus (Protocol) Peng Z, Chen XQ, Gong SS, Chen CF This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The CochraneLibrary 2012, Issue 4 Low-level laser therapy for tinnitus (Protocol)Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Med-pace.comAm J Physiol Gastrointest Liver Physiol 306: G796–G801, 2014.
First published March 13, 2014; doi:10.1152/ajpgi.00130.2013.
Prokinetic effects of mirtazapine on gastrointestinal transit Jieyun Yin,1 Jun Song,1 Yong Lei,3 Xiaohong Xu,3 and Jiande D. Z. Chen1,2,3
1Division of Gastroenterology, University of Texas Medical Branch, Galveston, Texas; 2Ningbo Pace Translational Medical
Research Center, Ningbo, China; and 3Veterans Research and Education Foundation, VA Medical Center, Oklahoma City,
Submitted 26 April 2013; accepted in final form 24 February 2014 Yin J, Song J, Lei Y, Xu X, Chen JD. Prokinetic effects
tion (4). Currently, there is lack of effective medications for of mirtazapine on gastrointestinal transit. Am J Physiol Gastro- treating both upper and lower GI symptoms.
intest Liver Physiol 306: G796 –G801, 2014. First published March Antidepressants are often prescribed in patients with IBS or 13, 2014; doi:10.1152/ajpgi.00130.2013.—Mirtazapine is a norad- FD (7, 17, 24). Their efficacy on treating IBS may be attributed renergic and specific serotonergic antidepressant. The aim of this to a reduction in visceral sensation and a relief of depression study was to investigate the effects of mirtazapine on gastrointestinal (5). The rationale for the use of antidepressants in FD was motility in dogs, including solid gastric emptying, antral and small considered to reduce the severity of psychological symptoms: intestinal contractions, and small intestinal and colonic transit. Six central analgesic actions and local pharmacological actions on dogs were implanted with two cannulas located at the duodenum and the upper gut (38). However, the effects of antidepressants on the ascending colon; another six dogs were implanted with gastric the GI motility have not been reported frequently. Mirtazapine cannula 6 cm proximal to the pylorus. Mirtazapine 45 mg wasadministered orally 90 min before the study. We found that 1) was reported to act on both noradrenergic and serotonergic Mirtazapine accelerated gastric emptying during the entire 3 h in systems, suggesting a brand-new antidepressive mechanism normal dogs (P ⬍ 0.04) and accelerated delayed gastric emptying compared with other antidepressants. It increases the release of induced by rectal distention (P ⬍ 0.04). 2) Mirtazapine restored norepinephrine (NE) and serotonin (5-hydroxytryptamine, impaired gastric tone and accommodation induced by rectal distention 5-HT) by blocking presynaptic ␣2-adrenergic receptors (11, (P ⬍ 0.05). 3) No significant changes were noted in small intestinal 16). Recently, it was reported that mirtazapine reduced visceral contractions or transit with mirtazapine (P ⬎ 0.1). 4) Mirtazapine hypersensitivity and accelerated liquid gastric emptying in rats accelerated colonic transit at 2 and 4 h but not 6 h. The geometric with neonatal colon sensitivity (42). Clinic case report showed center was increased from 1.9 ⫾ 0.6 to 3.0 ⫾ 0.5 and 3.9 ⫾ 0.5 to that mirtazapine was effective in treating severe gastroparesis 4.7 ⫾ 0.1 at 2 and 4 h respectively (P ⫽ 0.04 vs. corresponding unresponsive to the conventional prokinetic treatment (29); in control). In conclusion, mirtazapine improves gastric emptying in a patient with diabetic gastroparesis who is recalcitrant to healthy dogs and normalizes rectal distention-induced delay in gastric first-line treatment, mirtazapine improved gastroparetic symp- emptying and accelerates colon but not small intestinal transit in toms (20). We therefore hypothesized that mirtazapine might healthy dogs. Clinical studies are warranted to assess the effects of have a prokinetic effect on GI motility.
mirtazapine on gastrointestinal motility and sensory functions in The aim of this study was to investigate the effect of patients with functional gastrointestinal diseases.
mirtazapine on GI motility in a canine model under normal antidepressant; gastrointestinal motility; gastric emptying; colonic conditions and during rectal distention. Experiments were transit; rectal distention designed to assess the possible prokinetic effects of mirtazap-ine on solid gastric emptying and on small intestinal andcolonic transit.
DELAYED GASTRIC EMPTYING IS reported frequently in variousgastrointestinal (GI) motility disorders, such as gastroesopha- MATERIALS AND METHODS
geal reflux disease, functional dyspepsia, and gastroparesis (25,28, 35). Delayed gastric emptying is associated with upper Animal Model and Surgical Procedures gastric symptoms such as nausea, vomiting, fullness, bloating, Twelve healthy female hound dogs (22–26 kg) were used. Under and early satiety (25). Prokinetics are the first-line medicine for general anesthesia, in six of the dogs, two cannulas were implanted in treating delayed gastric emptying. However, there is a poor each animal: one at the duodenum, 20 cm distal to the pylorus for the correlation between the acceleration of gastric emptying and assessment of solid gastric emptying and small intestinal motility, and the improvement of gastric symptoms with prokinetics (27).
the other at the ascending colon, 6 cm distal to the cecum for the Upper GI symptoms are common in patients with lower GI measurement of colonic motility. In the other six dogs, a gastric motility disorders. It is reported that 30 –50% of patients with cannula was implanted at the anterior wall of the stomach 6 cmproximal to the pylorus for assessing gastric tone and accommodation.
functional GI disorders had both functional dyspepsia (FD) and The study was initiated after the dogs were completely recovered from irritable bowel syndrome (IBS) (23, 37). Patients with consti- the surgery, usually 2 wk after the operation. The study was approved pation-dominant IBS reported significantly more overall GI by the Animal Care and Use Committee at both the University of symptoms compared with the patients with diarrhea-dominant Texas Medical Branch at Galveston, Texas, and VA Medical Center, IBS (37). One study has reported that 90% patients with Oklahoma City, Oklahoma.
overlapping symptoms exhibited rectal intolerance to disten- Experiment 1: assessment of complete gastric emptying of solid. Address for reprint requests and other correspondence: J. Yin, Division of Gastroenterology, Route 0655, Galveston, TX 77555-0655 (e-mail: This experiment was performed in six dogs with a duodenal cannula.
Each dog was studied in one session. The purpose of this session was 0193-1857/14 Copyright 2014 the American Physiological Society MIRTAZAPINE ON GASTROINTESTINAL MOTILITY to measure the total gastric emptying of solids and to determine the The appearance of phenol red in the colonic collection was verified by percentage of gastric chyme we were able to collect for complete spectrophotometer after the experiment.
gastric emptying. The experiment was needed because some gastric Experiment 5: effects of mirtazapine on colon transit. Each dog was chyme might bypass the duodenal cannula and flow distally to the studied in two randomized sessions with an interval of 3–5 days: small intestine. After an overnight fast, each dog was fed with 375 g control and mirtazapine. After an overnight fast, mirtazapine 45 mg of solid dog food (413 kcal, Pedigree, Chopped Chicken). Immedi- was administered orally 1.5 h prior to the experiment. The experiment ately after the ingestion of the test meal, the duodenal cannula was was initiated immediately after the insertion of a capsule containing opened for collecting gastric chyme emptied from the stomach. The 24 radiopaque markers (Sitzmarks, Konsyl Pharmaceuticals, Easton, chyme was collected every 15 min for the first hour and every 30 min MD) through the colonic cannula. Before inserting the Sitzmarks, we for subsequent hours. The collection was continued for about 8 h until flushed the colon gently with 20 ml saline through the colonic the completion of gastric emptying (nothing except secretion was cannula. The capsule was dissolved in the colon within 10 min.
collected from the cannula for a period of 30 min). The amount of Abdominal X-ray was performed at 2, 4, and 6 h after the insertion of total collections was defined as 100% gastric emptying.
the capsule. To avoid possible stress effects, the animals were accli- Experiment 2: effects of mirtazapine on solid gastric emptying. The mated to X-ray film taking several times a week before the initiation same six dogs from experiment 1 were used in this experiment. Each of the colon transit test.
dog was studied in four sessions on separate days in a randomizedorder: control, mirtazapine (Remeron, Rockford, IL), rectal distention Measurements and Analyses (RD), and RD ⫹ mirtazapine. In the control session, no medicationwas given. Since our aim was to study the effect of mirtazapine on GI Measurement of solid gastric emptying. The collected chyme sam- transit, and antidepressants are often used to treat patients with ples from the duodenal cannula were centrifuged for 20 min (3,000 functional GI diseases. Clinically, the tablet of mirtazapine is mixed rpm). After centrifugation, each sample was placed in a ⫺20°C with the vehicle; it is therefore more relevant for us to compare the refrigerator for 4 h and then kept for 30 – 45 min at room temperature; difference between the use of mirtazapine tablets and no medication at in this way, the total sample in each tube was completely transferred.
all. The method of gastric emptying was the same as in experiment 1 The entire precipitate of each collection was then taken out, placed in except that the total measurement time was 3 h; the duration was a paper plate, and dried in air for a few days until there were no chosen on the basis of a previous study indicating that more than 80% changes in weight. The percentage of gastric emptying for each of the solids were emptied during the first 3 h (40). Mirtazapine (45 collection was calculated by using the following formula: % gastric mg) was administered orally 1.5 h prior to the meal. The dose of 45 emptying for each collection ⫽ Wn/Wt⫻100%, where Wn was the mg was chosen on the basis of the dosage used in clinic (30 mg/day) dried weight of the collection and Wt was the total dried weight of all (7); since the dosage of 30 mg/day was for chronic treatment and the samples collected in the same dog in experiment 1 (40). This normal- present study was acute, we chose a higher dose of 45 mg. The ized percentage of gastric emptying compensated for any possible loss half-life of mirtazapine was reported to be 14 ⫾ 3 h with a single oral of ingested food, such as bypass of gastric chyme to the distal small dose of 45 mg (19). In the two sessions with RD, RD was performed intestine and any absorption that might have occurred before the 60 –90 min after the meal. From preliminary studies, we observed that collection from the duodenal cannula.
gastric emptying of solid was the fastest 60 –90 min after the meal and Measurement of gastric tone and accommodation. Gastric tone was therefore RD was performed during that period (40). RD was achieved assessed from the measured gastric volume. At the constant operating by the inflation of a latex balloon inserted into the rectum with 120 ml pressure, an increase in gastric volume reflects a decrease in gastric tone, and vice versa. Gastric accommodation was calculated by the Experiment 3: effects of mirtazapine on gastric tone and difference in gastric volume before and after a meal.
accommodation. The experiment was performed in six dogs with the Measurement and analysis of small intestinal contractions. Small gastric cannula. Each dog was studied for four sessions in a random- intestinal contractions were measured by the same manometric sys- ized order: control, mirtazapine (45 mg), RD, and RD ⫹ mirtazapine tem. All pressure sensors were located in the jejunum with the most (45 mg). Gastric tone and accommodation were assessed using an proximal one 15 cm distal to the duodenal cannula. Intestinal con- established method of Barostat (Distender Series IIR, G & J Electron- tractions measured from the middle sensor, which was 25 cm distal to ics, Willowdale, Ontario, Canada) (36, 41, 45). Gastric volume was the duodenal cannula, showed the best quality and were chosen to be recorded for 30 min in the fasting state and 30 min after a liquid meal analyzed (43), from 0 to 60 min.
(237 ml, 240 kcal, Boost) in the sessions without RD, and for 60 min Measurement of colonic transit. Colonic transit was assessed by in the fasting state and 60 min after the liquid meal in the sessions counting the numbers of radiopaque markers from X-ray films in with RD, in which RD was performed during the second 30-min different segments of the colon at different time points. The colon was fasting period and first 30-min postprandial period.
divided into five segments, including ascending colon (segment 1), Experiment 4: effects of mirtazapine on small intestinal contrac- transverse colon, splenic flexure, descending colon, and rectum (seg- tions and transit. This experiment was performed in the same six dogs ment 5); the markers expelled out from the anus were considered to be as in experiment 1. It consisted of two sessions on 2 separate days in in segment 6. The geometric center (GC) of the markers was used to a randomized order: control and mirtazapine 45 mg. After an over- represent colon transit and calculated as follows: night fast, each dog was fed with a 375-g solid meal to induce postprandial small intestinal contractions. Small intestinal contrac- n n) ⁄ 24 for n ⫽ 1, 2, 3, 4, 5, 6 tions were then recorded for 60 min after the meal.
where Pn was the number of radiopaque markers in the nth segment Small intestinal transit was assessed simultaneously with gastric and n was the number of the segment.
emptying in experiment 1 in two of the sessions: control and mir-tazapine. Immediately after the meal, a 30-ml solution with phenol red (0.5 mg/ml, dissolved in saline) was injected through the duodenalcannula, then 50 ml saline was injected every 30 min until the end of All data are presented as means ⫾ SE. One-way ANOVA was used the experiment; these saline injections were used to offset the diver- to investigate differences in gastric emptying and GC at different time sion of gastric secretion and chyme from the duodenum cannula.
points among various sessions. Paired t-test was used to evaluate Samples through the colonic cannula were collected every 15 min differences in antral contractions and small intestinal motility between during the experiment and small intestinal transit was determined by control and mirtazapine. A P value of ⬍ 0.05 was considered the time of first appearance of phenol red from the colonic cannula.
AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00130.2013 • www.ajpgi.org MIRTAZAPINE ON GASTROINTESTINAL MOTILITY Effects of Mirtazapine on Small Intestinal Transit and * P < 0.04: RD vs. Mirt.+RD # P < 0.04: Control vs. Mirt.
Mirtazapine had no effect on either small intestinal transit or contractions. The small intestinal transit, represented by the first appearance of phenol red in the colon cannula, was not different between the control and mirtazapine sessions (137.8 ⫾ 19.3 min vs. 150.0 ⫾ 17.4 min, P ⫽ 0.3, Fig. 4). Neither was there a difference in the small intestinal contractions between the two sessions. The postprandial small intestinal contractile index was 10.6 ⫾ 1.4 mmHg in the control session and 13.6 ⫾ 3.7 mmHg with mirtazapine (P ⫽ 0.2, Fig. 4).
Effects of Mirtazapine on Colonic Transit Fig. 1. Effects of mirtazapine (Mirt.) on solid gastric emptying. Mirtazapinesignificantly accelerated gastric emptying in the normal condition (P ⬍ 0.04).
Mirtazapine accelerated colonic transit at 2 and 4 h after the In addition, mirtazapine normalized delayed gastric emptying in dogs with insertion of the markers from the colon cannula. As shown in rectal distention (RD) (P ⬍ 0.04).
Fig. 5, the GC was increased from 1.9 ⫾ 0.6 to 3.0 ⫾ 0.5 at 2h and 3.9 ⫾ 0.5 to 4.7 ⫾ 0.1 at 4 h (P ⫽ 0.04, control vs.
mirtazapine at both time points). At 6 h, the GC became similar between the two sessions since most of the markers were in the Effects of Mirtazapine on Solid Gastric Emptying and Antral rectum (5.0 ⫾ 0.1 vs. 5.0 ⫾ 0.1, P ⫽ 0.5).
Under normal condition without RD, mirtazapine acceler- In the present study, we have found that mirtazapine accel- ated gastric emptying during the entire 3-h experimental period erated solid gastric emptying in dogs with or without RD.
(Fig. 1). Compared with the control session, gastric emptying Mirtazapine also accelerated colonic transit but showed no was accelerated with mirtazapine by 48.1% at 90 min (P ⬍ effects on small intestinal transit or contractions.
0.01), 38.2% at 120 min (P ⫽ 0.02), and 17.7% at 180 min Delayed gastric empting is common in patients with GI (P ⫽ 0.03).
motility disorders, such as FD and gastroparesis. Treatment RD during 60 –90 min substantially delayed gastric empty- options for FD and gastroparesis are very limited. Although ing (Fig. 1). Gastric emptying was reduced with RD by 46.2% prokinetics stimulate peristalsis and improve gastric pump at 90 min (P ⬍ 0.01), 45.2% at 120 min (P ⬍ 0.001), and functions by enhancing antral contractility, electrical rhythm, 36.3% at 180 min (P ⬍ 0.01). As shown in Fig. 1, mirtazapine and/or antroduodenal coordination, sometimes they do not accelerated gastric emptying during 45– 60 min without RD result in significant symptom improvement (27, 34). This is and normalized RD-induced delayed gastric emptying during because patients with delayed gastric emptying often have 90 –180 min: the percentages of gastric emptying during 90 – impaired gastric accommodation and/or visceral hypersensitiv- 180 min in the session with RD and mirtazapine were compa- ity. The failure of certain prokinetics on improving symptoms rable to those in the control session without RD. The acceler- may be attributed to their detrimental effects on gastric accom- ation before the administration of RD confirmed that mirtazap- modation and/or ineffectiveness in improving visceral hyper- ine was able to increase gastric emptying even under the normal condition.
Because of the lack of effective therapies on functional GI Consistent with the findings on gastric emptying data, mir- motility disorders, antidepressants are commonly prescribed in tazapine enhanced antral contractions in the fed state. Asshown in Fig. 2, the contractile index (sample-by-sampleaverage of manometric data) was increased from 8.0 ⫾ 0.7 mmHg in the control session to 12.9 ⫾ 3.0 mmHg with mirtazapine (P ⫽ 0.03).
Effects of Mirtazapine on Gastric Tone and Accommodation Mirtazapine had no effects on gastric tone or gastric accom- modation in the normal physiological condition (without RD).
RD significantly reduced both gastric tone and gastric accom- modation, whereas mirtazapine partially blocked the inhibitoryeffects of RD on gastric tone and gastric accommodation. The Contractile Index
RD-induced increase in gastric volume in the fasting state was 253.6 ⫾ 61.1% without mirtazapine and 97.8 ⫾ 23.1% with mirtazapine (P ⫽ 0.03). Gastric accommodation was 149.4 ⫾ Fig. 2. Effects of mirtazapine on postprandial antral contractions in dogs under 29.8 ml with RD and 290.9 ⫾ 45.7 ml with RD plus mirtazap- normal condition. Mirtazapine significantly enhanced antral contractions com- ine (P ⫽ 0.012) (Fig. 3).
pared with the control session (P ⫽ 0.03).
AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00130.2013 • www.ajpgi.org
MIRTAZAPINE ON GASTROINTESTINAL MOTILITY Fig. 3. Effects of mirtazapine on gastricsensitivity to rectal distention. Rectal disten-tion significantly reduced gastric tone andaccommodation. Mirtazapine restored rectaldistention induced reduced gastric tone (A)and accommodation (B) (P ⬍ 0.05).
clinic practices, such as tricyclic antidepressants and selective rectal distention was not suitable for such a study; rectal serotonin reuptake inhibitor. It is conceivable to treat func- distention was performed to induce delayed gastric emptying; tional GI disorders with antidepressants because these drugs however, it was only convenient for assessing acute effects but are used to treat depression and reduce chronic pain. However, not adequate for a chronic study.
the evidence is conflicting and there is lack of large controlled Overlapping syndrome is common in clinic practice; upper trials. Mirtazapine is a noradrenergic and specific serotonergic GI dyspepsia symptoms are often present in patients with lower antidepressant, a newer class of antidepressant that is charac- GI tract disorders, such as constipation. The mechanisms have terized by a potent antagonism of presynaptic ␣2 adrenergic not been elucidated and there is lack of satisfactory treatment receptors on both NE and serotonin neurons (11). While options for overlapping syndromes. Fecal or gas distention treating depression, mirtazapine was noticed to be beneficial might be one of the major contributing factors in producing for bowel movement in IBS patients (39). In patients with upper GI symptoms in patients with lower GI dysmotility.
severe gastroparesis unresponsive to the conventional proki- Rectal balloon distention was reported to induce upper GI netic treatment, refractory nausea and vomiting that persisted symptoms, inhibit gastric tone and accommodation, and delay for over 7 mo were improved dramatically within a few days of gastric emptying (2, 31, 44), and it is considered one of the once-daily mirtazapine dosing (29). In a previous study, we constipation models commonly used in the study of upper GI observed improvement of gastric emptying with mirtazapine in motor activities. In the present study, in addition to testing the colonic sensitized "IBS-like" rats (42). In the present canine effect of mirtazapine on solid gastric emptying in normal dogs, study, we found that mirtazapine improved gastric emptying,gastric accommodation, and colon transit; this was different RD was used to mimic fecal or gas stasis in the colorectal from what was reported in a clinical study in which mirtazap- region. We found that RD at 60 –90 min substantially delayed ine showed no effects on gastric emptying in healthy volun- gastric emptying from 90 min to 180 min, whereas mirtazapine teers (7). The difference might be attributed to the differences normalized RD-induced delayed in gastric emptying. More- in species (dogs vs. humans), dosage (45 mg vs. 30 mg), and/or over, mirtazapine restored RD-induced reduced gastric tone duration of the study (acute vs. chronic).
and accommodation. The changes of gastric sensitivity and There were at least two limitations in the present study: lack gastric emptying may explain the improvements of symptoms of dose-response study and absence of chronic repetitive study.
in patients with gastroparesis reported in the clinic practice.
A dose-responsive study was, however, performed in our The normalization of RD-induced delay in gastric emptying previous study investigating the ameliorating effect of mir- and the acceleration of colon transit suggest that mirtazapine tazapine on neonatal rectal distention-induced gastric hyper- may have a therapeutic potential for treating patients with sensitivity. The absence of any data on repetitive chronic study symptoms attributed to both upper and lower GI motility was attributed to the fact that the present canine model with Fig. 4. Effects of mirtazapine on small intestinal motility. The small intestinal transit was not dif- ferent between the control and mirtazapine ses- sions (P ⫽ 0.3) (A); neither was there a difference in small intestinal contractions between the con- trol and mirtazapine sessions (P ⫽ 0.2) (B).
AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00130.2013 • www.ajpgi.org MIRTAZAPINE ON GASTROINTESTINAL MOTILITY 1A receptor agonist has been shown to in- crease esophageal motility and colonic migrating motor com- plexes (14, 15). Accordingly, we speculate that the prokinetic effects of mirtazapine observed in this study are attributed to increased release of 5-HT (mainly via the actions of 5-HT2Cand 5-HT1A) and the blockage of ␣2 adrenergic receptors.
The ameliorating effects of mirtazapine on rectal distention- induced impairment in gastric motility (tone, accommodation, contractions, and emptying) are believed to be attributed to both its prokinetic effects and its inhibitory effects on rectaldistention-induced hypersensitivity. In the present study, mir- tazapine blocked the rectal distention-induced inhibitory ef- fects on gastric motility. In a previous study, mirtazapine was Fig. 5. Effects of mirtazapine on colonic transit. Mirtazapine accelerated found to reduce rectal distention-induced gastric hypersensi- colonic transit 2 and 4 h after the insertion of the radiopaque markers (P ⫽ tivity (42).
Interestingly, although mirtazapine was found to have the prokinetic effect on both gastric emptying and colonic transit,it showed no effects on small intestinal contractions or transit The effect of mirtazapine on colonic transit had not been in the normal dogs. In this study, intestinal transit was per- studied before. It is known that many IBS patients display formed simultaneously with gastric emptying, and gastric visceral hypersensitivity during colorectal distention (26, 30, chyme emptied from the stomach was diverted out through the 33). In an earlier study we reported improvement on visceral duodenal cannula. One might argue that this was not physio- hypersensitivity with the administration of mirtazapine in co- logical because the intestine was not exposed to nutrients. Our lonic sensitized rats (42); however, its effect on the colonic rationale for such a special design was based on following transit was not investigated. In the present study, we found that considerations. Under normal physiological condition, intesti- mirtazapine accelerated colonic transit in normal dogs. The nal transit is influenced by gastric emptying, i.e., how fast combined effects of mirtazapine on visceral hypersensitivity nutrients are delivered from the stomach to the small intestine.
and colon transit may play a role in treating symptoms of IBS, While designing the study, we anticipated that mirtazapine especially in constipation-dominant IBS. It has to be men- would alter gastric emptying and, therefore, the effect of tioned that in the present study acceleration of colonic transit mirtazapine on gastric emptying would be a confounding factor by mirtazapine was observed in normal dogs rather than a in studying the effect of mirtazapine on intestinal transit. To canine model of constipation.
eliminate this confounding factor, we decided to divert all Mirtazapine is an adrenoceptor antagonist with preferential gastric chyme and perform the test simultaneously with gastric affinity for presynaptic ␣2 adrenoceptors and low affinity for emptying by ingesting saline mixed with phenol red to the 1 adrenoceptors (10). Blockade of ␣2 receptors by mirtazap- small intestine via the duodenal cannula. Although gastric ine enhances both noradrenergic and serotonergic transmission chyme was diverted, the small intestinal motility pattern ob- (11). Although the increase in NE potentially inhibits GI served during the test was similar to the postprandial pattern.
motility, mirtazapine may enhance GI motility for the follow- The mechanisms underlying why mirtazapine had no effect on ing reasons: 1) Blockage of ␣2 receptors is expected to increaseGI motility. In one previous study, it was shown that pretreat- small bowel transit or contractions was not clear. It could be ment of mirtazapine antagonized the effect of clonidine (21), due to the differences in the coupling of ␣2 receptors to whereas clonidine is known to delay gastric emptying and adrenergic and serotonergic neurons in the small bowel. Fur- induce constipation. 2) Enhancement of serotonin transmission ther mechanistic studies are needed to investigate why there due to blockade of ␣ were differences in the effects of mirtazapine among different 2 receptors by mirtazapine increases 5-HT release. Mirtazapine has a high affinity for serotonergic 5-HT organs of the gut.
receptor subtypes, especially 5-HT In conclusion, mirtazapine improves gastric emptying in 2A and 5-HT2C (9). 5-HT2C was known to regulate GI motor activity and it was reported to healthy dogs, normalizes rectal distention-induced delay in stimulate phasic contractions and phase III activity in canine gastric emptying and accelerates colon transit in healthy dogs.
jejunum (19, 22). Antidepressants with a strong affinity for Clinical studies are warranted to assess the effects of mirtazap- ine on GI motility and sensory functions in patients with 2C receptor are reported to be associated with weight gain (13). Studies have shown that more than 10% of patients functional GI diseases.
experience substantial weight gain during mirtazapine treat-ment and more than 10% patients have been noticed to have an increased of appetite (1). 3) Facilitation of NE transmission No conflicts of interest, financial or otherwise, are declared by the author(s).
due to blockade of ␣2 receptors by mirtazapine may furtherenhance serotonin transmission due to enhancement of 5-HT1A function (3, 32) mediated via ␣2 heteroreceptors (12); blockageof ␣ J.Y. and J.D.C. conception and design of research; J.Y., J.S., Y.L., and X.X.
2-adrenergic heteroreceptors located on the 5-HT terminals performed experiments; J.Y., J.S., Y.L., and X.X. analyzed data; J.Y. and removes the tonic inhibition caused by endogenous NE. Fur- J.D.C. interpreted results of experiments; J.Y. prepared figures; J.Y. drafted thermore, mirtazapine has been reported to block 5-HT3 recep- manuscript; J.Y. and J.D.C. edited and revised manuscript; J.Y. and J.D.C.
tors with a potency similar to its effects on ␣2 receptors (8, 18).
approved final version of manuscript.
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AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00130.2013 • www.ajpgi.org
INF RMATION MINDS MAKE MOLECULES – MOLECULES MAKE SENSE Årgang 6, nr. 4 April 2014 http://inf.ku.dk FRA NEUROBIOLOGISK KAFFE TIL NY INDSIGT Af Albert Gjedde dimittend fra den neurobiologiske kaf- emne for neurovidenskaben i Køben- feklub, Martin Lauritzen, og hans med- havn var enheden genstand for ud- Den neurobiologiske kaffeklub var kæ-