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*Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan;
Department of Anesthesiology, National Defense Medical Center/Tri-Service General Hospital, Taipei, Taiwan;
Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan; and
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
Address correspondence and reprint requests to Shung-Tai Ho, MD, MS, Department of Anesthesiology, National Defense Medical Center/Tri-Service General Hospital, Rm. 8113, No. 161, Sec. 6, Minchiuan E. Rd., Taipei 114, Taiwan. Address e-mail to painlab{at}tpts5.seed.net.tw
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Abstract |
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IMPLICATIONS: Dexamethasone has an antiemetic property, but the mechanism remains unclear. An oscillographic vomiting model was used in unanesthetized and decerebrated cats to demonstrate that a stereotaxic microinjection of dexamethasone had an antiemetic effect against xylazine-induced emesis by acting on glucocorticoid receptors in the bilateral nuclei tractus solitarii.
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Introduction |
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The medulla may be the center for the regulation of emetic and antiemetic responses (9). The nucleus tractus solitarius (NTS) and the area postrema (AP) in the medulla are believed to be important in the regulation of these responses (10). Moreover, large quantities of glucocorticoid receptors are in these two areas (11). Hence, we assume that the NTS and the AP are the main regions in which dexamethasone exerts its central antiemetic action. The aim of this study was to evaluate whether dexamethasone had a central antiemetic action and to determine the most likely site of its action in cats.
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Methods |
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Each cat was fasted overnight and placed in a sealed anesthetic chamber after being weighed on the day of the experiment. The animals were anesthetized with 4% pure-oxygen-gasified halothane via a small-animal anesthetic apparatus. The cats were then taken out of the chamber, and endotracheal tubes (inner diameter, 3.0–4.5 mm) were fixed to their mouths to decrease the concentration of halothane to 1% and maintain an anesthetic effect. For establishment of the oscillographic vomiting model (14), the right external jugular vein was separated; a central venous catheter was inserted and advanced into the precava to measure intrathoracic pressure. Likewise, a two-lumen central venous catheter was inserted into the right femoral vein, and the proximal lumen was advanced into the abdominal postcava to measure intraabdominal pressure while the distal lumen was prepared for injection. A polyethylene catheter was then placed in the right femoral artery to measure arterial blood pressure. All catheters were filled with saline containing heparin 100 U/mL to avoid intravascular coagulation. These three catheters were connected to a pressure transducer, which was connected to a polygraph, which displayed continuous online changes of arterial blood pressure, intrathoracic pressure, and intraabdominal pressure. The signals were stored on a digitized videotape recorder for future analysis.
The three-barrel and four-barrel multibarrel micropipette (tip diameter, approximately 30 µm), which was made by heating a glass micropipette puller (PE-2M; Narishige, Tokyo, Japan), was used. One of the barrels of the micropipette was filled with 3 M NaCl solution, and a platinum wire was placed as an electrode and connected to an electrical stimulator to input rectangular pulses (rate, 80 Hz; volts, 50–100 µA; duration, 0.5 ms) that stimulated nervous tissue. The other barrel was filled with 1% pontamine sky blue, which was prepared for confirmation of the microinjection point via a 100-nL injection after completion of the antiemetic experiment. The third barrel was filled with various concentrations of dexamethasone; the fourth barrel was filled with mifepristone (a glucocorticoid receptor antagonist) and given if necessary. The micropipette used for injection of the drugs was connected to a pneumatic pump through a polyethylene tube. During the drug administration, the nitrogen gas pressure was adjusted via pneumatic pump. The movement of the fluid meniscus in the micropipette was observed under the microscope; drug dosage was controlled and slowly pressed into the medullary nuclear area under investigation.
The cats were pronated, their heads were fixed in the stereotaxic apparatus, and part of the occipital bones were removed with bone forceps. The rear of the cerebellum was slightly lifted, and the obex at the tip of the fourth ventricle was exposed. The multibarrel micropipette was placed on the stereotaxic apparatus at 34° and perpendicular to the floor of the fourth cerebral ventricle to give the microinjection. The obex was set as the zero point on the coordinated axis. The coordinates of NTS were then within the range of 0.5–1.0 mm anterior to obex, 1.0–2.0 mm lateral to the midline, and 0.5–1.5 mm deep to the surface (15–17). As in our previous studies (16,17), the nuclear area was first functionally identified by electrically stimulating the NTS, which was capable of decreasing the mean arterial blood pressure by 20 mm Hg. Microinjection of the drug was then given. This nuclear area was located at the posterior third and was related to gastrointestinal and cardiovascular responses.
One percent halothane was provided until decerebration was accomplished. Halothane concentrations in the cat’s breath were monitored with an end-tidal gas monitor (Capnomac Ultima; Datex-Ohmeda, Helsinki, Finland) during the process. The complete decerebration procedure has been described (18). First, the bilateral external carotid artery was ligated at the anterior portion where the lingual artery did not branch away. The vertical median skin was dissected, the parietal bone was removed with bone forceps, part of the cerebrum was extracted by a pulsometer, and the superior colliculi were exposed. The connection between the cerebrum and the brainstem was then cut off at the intercollicular level, followed by incarceration of the basilar artery with a silver clip to prevent bleeding. From then on, the posterior brain tissue blood supply was drawn from the vertebral arteries.
To evaluate whether dexamethasone has a central antiemetic action and to discover its site of action, the following studies (Parts I, II, III, and IV) were performed. The objective of Part I was to evaluate whether dexamethasone has a central antiemetic action when injected into the bilateral NTS in unanesthetized and decerebrated cats. After anesthesia with 1% halothane, 100 nL of saline was injected into the bilateral NTS in the control group, whereas 100 nL of various doses of dexamethasone (1, 0.1, and 0.01 µg) were injected into the bilateral NTS in the experimental group individually. Then, the micropipettes were removed, and the cats were decerebrated and kept unanesthetized. After 1 h, xylazine (0.66 mg/kg IM) was injected to induce vomiting (12,13). The interval between microinjection of dexamethasone and injection of xylazine was 1.5 to 2 h in this study. Simultaneously, the vomiting variables (latency [the time until onset of the first emetic episode] and episode [frequency of emesis]) within 30 min were recorded and analyzed with an oscillographic vomiting model. During the experiment, an IV infusion of lactated Ringer’s solution was given to replenish water content and to keep mean arterial blood pressure at >90 mm Hg. CO2 concentration was monitored with a end-tidal gas monitor (Capnomac Ultima), and ETCO2 was kept at 4%–6%. The anal temperature was kept at 36°C–37°C via a radiant heat lamp and mat.
The objective of Part II was to explore whether dexamethasone acted on bilateral NTS via glucocorticoid receptors to prevent xylazine-induced emesis. The experimental method was similar to that of Part I. Ten minutes before microinjection of 100 nL of dexamethasone (0.1 µg), which had been demonstrated as an effective dose of dexamethasone in Part I, 100 nL of the equivalent dose of mifepristone (0.1 µg) was injected into the bilateral NTS at the same coordinates on the brainstem. Similarly, xylazine was used to induce emesis 1 h after the microinjection of dexamethasone, and an oscillographic vomiting model was used to record vomiting variables. To further examine whether mifepristone itself can influence xylazine-induced emesis, we mimicked the methods of Part I. Microinjections of 100 nL of mifepristone (0.1 µg) were administered in the bilateral NTS. Similarly, xylazine was used to induce vomiting an hour later, and an oscillographic vomiting model was used to record vomiting variables.
The objective of Part III was to explore whether dexamethasone had a preventive effect on xylazine-induced emesis via unilateral NTS. The method mimicked that of Part I. Dexamethasone (100 nL) was injected into the unilateral (left side, n = 3; right side, n = 3) NTS at doses of 0.1 and 1 µg, which have been demonstrated to be effective doses to prevent xylazine-induced emesis. Similarly, xylazine was used to induce vomiting 1 h later, and an oscillographic vomiting model was used to record vomiting variables.
Because the AP, located on the dorsal surface of the medulla at the caudal end of the fourth ventricle, also plays an important role in regulating the emesis reflex, the objective of Part IV was to determine whether dexamethasone had an antiemetic effect on AP in unanesthetized and decerebrated cats. The same dose (5 µg in 5 µL) as the effective dose (0.1 µg in 0.1 µL) of dexamethasone in Part I or a 10-fold dose (50 µg in 5 µL) were respectively added into 2 cottonoid pledgets (0.5 mm wide x 3.0 mm long x 0.5 mm thick) that were placed on the AP under the microscope in advance (19). Two cottonoid pledgets were removed from under the microscope 10 min later. Xylazine (0.66 mg/kg IM) was injected to induce vomiting an hour later, and an oscillographic vomiting model was used to record vomiting variables within 30 min.
Xylazine was purchased from Bayer (Leverkusen, Germany) and was dispensed in saline at proper doses. Dexamethasone 21-phosphate disodium was purchased from Sigma (St. Louis, MO) and was dispensed in saline. Mifepristone was purchased from Sigma and was dissolved in ethanol followed by dispensing in saline to a final solution containing 2% ethanol (vol%).
The brain was removed after each experiment and fixed in 4% formaldehyde for 36 h. Then the brain was washed with phosphate-buffered saline and frozen at –70°C for 10 min until hard. The brain was transected in a cryostat with the slice thickness set at 50 µm and was dyed in cresyl violet. The microinjection points could be confirmed by traces of pontamine sky blue that corresponded with the coordinates of the stimulation points in the records and brain drawings of the cats (15).
The vomiting variables, including the latency and the frequency of vomiting, were expressed as mean ± SD. Wilcoxon’s signed rank test was used to compare the differences in the vomiting variables after microinjection of drugs. P < 0.05 was considered statistically significant.
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Results |
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The Part III experiment (Table 2) showed that microinjections of 0.1 and 1 µg of dexamethasone into either side of the NTS did not have a significant influence on the latency or the frequency of vomiting.
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Discussion |
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Surprising findings were that microinjection of dexamethasone into the unilateral NTS and the AP did not have a significant influence on xylazine-induced emesis. We suggest two possible explanations. First, xylazine exerts its emetic action through an activation of the chemoreceptive trigger zone (CTZ) in the AP (13). There are many nerve connections between the CTZ in the AP and the bilateral NTS (20,21). When the CTZ is activated by an emetic, the signal is conveyed through the bilateral NTS to drive the center that triggers vomiting (21). Thus, microinjection of dexamethasone in the unilateral NTS only has no effect on xylazine-induced emesis. Second, the bilateral NTS had been demonstrated as a termination site of various emetic inputs, including CTZ in AP, vagus nerve afferents, and the vestibular systems (9,10). Therefore, several authors have hypothesized that the bilateral NTS may be the common final pathway that leads to the vomiting center (10). Moreover, large numbers of glucocorticoid receptors are in the bilateral NTS (11), and dexamethasone acts via glucocorticoid receptors, suggesting that the location of antiemetic action of dexamethasone is possibly related to the bilateral NTS in this nervous pathway. Consequently, perhaps dexamethasone completes its antiemetic action via glucocorticoid receptors in the bilateral NTS and not the AP.
Dexamethasone in the central nervous system can influence the actions of neurotransmitters (22). There probably are many kinds of vomiting-related neurotransmitters in the NTS, such as adrenaline, noradrenaline, dopamine, serotonin, histamine, and substance P (23). In our study, we further found that dexamethasone could modulate the vomiting response through its action on glucocorticoid receptors in the bilateral NTS. However, which one or several vomiting-related neurotransmitters in the NTS that dexamethasone will influence in the process awaits further elucidation.
Our previous study demonstrated that in cats, the single smallest effective dose of dexamethasone injected peripherally to prevent xylazine-induced emesis was 4 mg/kg (8). Moreover, it is generally accepted that the dose of direct microinjections into the nuclear area of the brainstem is approximately 1 in 1000 doses injected peripherally (24,25). This was also shown in our central blood pressure regulation experiment (26). Thus, doses ranging from 1 to 0.01 µg are regarded as microinjections of dexamethasone.
Because stereotaxic microinjections and placement of arterial and venous catheters cannot be performed in conscious animals and because anesthetics influence vomiting, we used an unanesthetized and decerebrated animal model. The animal was anesthetized via halothane inhalation and decerebrated. Halothane inhalation was immediately stopped after the operation, and we waited for an hour under end-tidal gas monitoring for the halothane to be exhaled. Because the loss of cerebral tissue attached to the central vomiting regulation action can be completed only in the brainstem (27), the animal cannot feel pain and loses conscious active movement, which makes it quietly accept the entire experiment.
In conclusion, this study demonstrated, in cats, that dexamethasone has a central antiemetic action and that dexamethasone exerts its central antiemetic action through activation of the glucocorticoid receptors in the bilateral NTS.
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