Antinociceptive actions of intravenous a2-adrenoceptor agonists in sheep

The antinociceptive activity of the intravenously administered alpha 2-adrenoceptor agonists, clonidine and xylazine, was measured in sheep using thermal and mechanical pressure threshold detection systems. Both drugs demonstrated clear antinociceptive activity for both forms of threshold stimuli and clonidine at 6 micrograms/kg i.v. was more potent and longer lasting than xylazine at 50 micrograms/kg i.v. The antinociceptive effects were reversed by idazoxan (0.1 mg/kg i.v.), but were not affected by naloxone at 0.2 mg/kg i.v. indicating that these effects were mediated by alpha 2-adrenoceptors.     

Depression of reticulo-ruminal motor functions through the stimulation of 012-adrenoceptors

Inhibition of the cyclical contractions of the reticulum and the rumen by detomidine (10-40 micrograms/kg, i.v.), xylazine (20-80 micrograms/kg, i.v.) and clonidine (2.5-10 micrograms/kg, i.v.) were compared in sheep and cattle housed individually in box stalls. Two alpha 2-adrenergic receptor blocking agents, tolazoline and yohimbine, were administered intravenously for prevention (0.1-0.4 mg/kg) or reversal (0.4-1.2 mg/kg) of these effects. Continuous recording of the reticuloruminal contractions and measurement of the volume of ruminal gas eliminated through the upper respiratory tract indicated that the three alpha 2-agonists inhibited the primary ruminal contractions associated with the reticular contractions. The occurrence of secondary ruminal contractions was also blocked in sheep, but only suppressed in cattle. The inhibition of reticulo-ruminal contractions was prevented or reversed competitively by the two alpha 2-blocking agents, suggesting an alpha 2-adrenoceptor mediation of the inhibition of cyclical motor activity of the reticulo-rumen. In contrast with tolazoline, yohimbine was unable to alleviate the accumulation of gas resulting from inhibition of the secondary ruminal contractions.     

Alpha-2 adrenoreceptors mediate clonidine-induced hypoinsulinaemia in sheep

Insulin and glucose concentrations in the blood of sheep were measured before, and up to 7 h after, feeding. The patterns reported by other workers were confirmed, namely: an early insulin concentration peak and decline in glucose concentration and, later, more prolonged changes. Intravenous injection of clonidine (2 micrograms/kg or 5 micrograms/kg) just before offering food caused hypoinsulinaemia and hyperglycaemia, abolishing the normal patterns. Administration of idazoxan (0.1 mg kg-1), an alpha-2 adrenoreceptor antagonist, before a 2 micrograms/kg dose of clonidine, completely blocked the effects of clonidine. By contrast, with prior injection of prazosin (0.1 mg/kg), an alpha-1 adrenoreceptor antagonist, the hypoinsulinaemia in response to clonidine still occurred and the hyperglycaemia appeared to be enhanced. The antagonists injected alone had only slight effects: idazoxan caused a slight hypoglycaemia and prazosin a slight hyperglycaemia. The results indicate that clonidine causes hypoinsulinaemia and hyperglycaemia by action on alpha-2 receptors. Possible mechanisms are discussed.     

Sedative effects of medetomidine in pigs.

Sedative effects of medetomidine, a potent selective and specific alpha 2-adrenoceptor agonist, were evaluated in pigs using 5 different doses (30, 50, 80, 100 and 150 micrograms/kg of body weight) and compared with those of xylazine (2 mg/kg). Atropine (25 micrograms/kg) was mixed with both drugs to prevent severe bradycardia. All drugs were administered intramuscularly. Medetomidine at a dosage of 30 micrograms/kg produced more potent sedation than xylazine. The depth of sedation induced by medetomidine was dose dependent within the range from 30 to 80 micrograms/kg. At 100 or 150 micrograms/kg, the depth of sedation was mostly the similar level to that at 80 micrograms/kg but the duration was prolonged. The degree of muscle relaxation produced by medetomidine also seemed to be dose dependent from 30 to 80 micrograms/kg and was stronger than that produced by xylazine. An increase in the duration of muscle relaxation was dose dependent up to 150 micrograms/kg. No analgesic effect was produced by xylazine, however moderate analgesia was obtained by medetomidine. There were no marked changes in heart rate and respiratory rate during the observation period in pigs of any groups, however mild hypothermia after the administration of both drugs was observed. From these results, medetomidine has a significant and dose-dependent sedative effects which are much more potent than that of xylazine, and a combination of 80 micrograms/kg of medetomidine and 25 micrograms/kg of atropine is suitable for sedation with lateral recumbency and moderate muscle relaxation without notable side effects in pigs.     

Cardiovascular and haemodynamic effects of intramuscular doses of xylazine in conscious sheep

OBJECTIVE: To determine if a commonly used analgesic dose of xylazine has detrimental cardiovascular or haemodynamic effects in sheep. DESIGN: A physiological study following intramuscular administration of xylazine. PROCEDURE: Xylazine (50 micrograms/kg) was injected intramuscularly into six healthy Merino ewes. For 60 min heart rate, mean arterial blood pressure and cardiac output were recorded; arterial blood samples for the measurement of blood gas tensions were also collected. RESULTS: There were no significant changes in heart rate, mean arterial blood pressure, cardiac output or arterial carbon dioxide tension. A slight degree of arterial hypoxaemia was noted with a 10% reduction in arterial oxygen tension values at 30 min. CONCLUSION: The minimal changes to cardiovascular and respiratory values in this study verify the safety of previously suggested analgesic dosing regimens for sheep. Previously reported hypoxaemic effects in sheep as a result of intravenous xylazine administration appear to be reduced as a result of intramuscular administration.     

A2-agonists in sheep: a review

OBJECTIVE: To review the use and adverse effects of alpha(2)-agonists in sheep. STUDY DESIGN: Literature review. MATERIAL AND METHODS: 'Pubmed' of the United States National Library of Medicine and 'Veterinary Science' of CAB International were searched for references relating sheep to alpha(2)-agonists. The bibliographies of retrieved articles were further scrutinized for pertinent references, and relevant articles were selected manually. RESULTS: Reports on the use of clonidine, xylazine, detomidine, romifidine, medetomidine and dexmedetomidine, MPV-2426 and ST-91 in sheep were found in the literature. Most of the studies described xylazine followed by medetomidine and clonidine. The literature on detomidine and romifidine in sheep was sparse. Reports included pharmacokinetic studies, evaluation of sedative, analgesic, and anaesthetic techniques with or without cardiovascular effects, and experimental investigations of adverse effects (mainly hypoxaemia) including the mechanisms of pulmonary oedema and impaired oxygenation after alpha(2)-agonist administration. CONCLUSIONS: A(2)-agonists are potent and effective analgesics in sheep. In combination with ketamine, they are frequently used for the induction and maintenance of anaesthesia, in this case analgesia is satisfactory. The degree of hypoxaemia which occurs with all commercially available alpha(2)-agonists is highly variable and depends on individual or breed-related factors; the most severe reactions occur after intravenous (IV) injection and during general anaesthesia. Clinical relevance Subclinical respiratory disease is common in sheep. Rapid IV injection of alpha(2)-agonists without supplementary oxygen should be avoided whenever hypoxaemia may be critical.     

Cardiopulmonary effects of dexmedetomidine in goats and sheep anaesthetised with sevoflurane

In sheep, alpha(2)-agonists can induce severe hypoxaemia. In goats, reports on changes in oxygenation are inconsistent. The aim of this study was to compare the cardiopulmonary effects of dexmedetomidine in six goats and four sheep anaesthetised with sevoflurane and maintained at approximately 1 minimal alveolar concentration. The animals were ventilated mechanically and held in an upright position to minimise the influence of positioning on pulmonary function. After baseline cardiopulmonary measures, 2 microg/kg dexmedetomidine was injected intravenously over one minute, and measurements were made for 120 minutes. In both species, respiratory resistance, alveolar dead space and shunt fraction increased and thoracic compliance decreased significantly; arterial, pulmonary arterial, pulmonary capillary wedge and central venous pressures increased and heart rate and cardiac output decreased significantly. Arterial oxygen tension decreased significantly, with no significant difference between the goats and sheep. Wide interindividual differences were observed in both the goats (mean [sd] 144 [149.1] mmHg, range 54.8 to 443.7 mmHg) and sheep (mean [sd] 129.8 [132.1] mmHg, range 33.7 to 352.8 mmHg), but the cardiovascular and respiratory changes were similar in the two species.     

Cardiopulmonary effects of clonidine, diazepam and the peripheral α2 adrenoceptor agonist ST-91 in conscious sheep

The cardiopulmonary effects of the intravenous administration of clonidine (15 μg/kg), ST-91 (30 μg/kg) and diazepam (0.4 mg/kg) were compared in five healthy sheep using a randomized cross-over design, to determine whether the hypoxaemic effects of α₂ adrenoceptor agonists are due to sedation, or to peripheral α₂ adrenoceptor stimulation. All three drugs significantly lowered arterial oxygen tension (PaO₂) levels within 2 min of their administration; however, clonidine and ST-91 produced long lasting and severe hypoxaemia with mean PaO₂ levels of ≈40 mm Hg and 50 mm Hg (5.3 kPa and 6.6 kPa), respectively. The fall in PaO₂ was considerably less with diazepam (63 mm Hg or 8.4 kPa at 2 min) and by 15 min the values did not differ from placebo treated animals. None of the drugs increased arterial carbon dioxide tension (PaCO₂) levels when compared to saline treatment and the acid base variables did not show any significant change. A significant increase was recorded in the packed cell volume of the ST-91 treated group throughout the study. Within 2 min of their administration, all drugs caused a significant increase in mean arterial pressure (MAP) as compared to the placebo treated group. The MAP remained significantly increased for 5 and 60 min after clonidine and ST-91 treatment, respectively. The study shows that ST-91 and clonidine produce a greater degree of hypoxaemia than occurs with diazepam sedation, and that the hypoxaemic effect of α₂ adrenoceptor agonists in sheep are mainly mediated by peripheral α₂ adrenoceptors.     

The effect of xylazine on plasma thromboxane B2 concentration in sheep

α₂-adrenoceptor agonist drugs can cause respiratory changes leading to a short period of hypoxaemia in sheep. It has been suggested that this is due to transient platelet aggregation and pulmonary microembolism. If platelet aggregation were to follow platelet activation in response to the administration of α₂ agonists, plasma thromboxane levels would be expected to rise. This study was carried out to measure plasma thromboxane B₂ concentrations before and after the intravenous administration of the α₂-agonist drug xylazine at a dose of 0.1 mg/kg. It was found that the plasma thromboxane concentration rose by 320% and, furthermore, the rise was prevented by the prior administration of atipamezole hydrochloride (0.125 mg/kg), an α₂-adrenoceptor antagonist.     

Involvement of α-adrenoreceptors in the regulation of omasal cyclic myoelectrical activity in sheep

In five conscious adult ewes at rest, chronically implanted with electrodes in the musculature of the omasal wall, intravenous (i.v.) infusion for 30 min of alpha 1- or alpha 2-adrenergic receptor blockers, prazosin (20 micrograms/kg/min) and yohimbine (30 micrograms/kg/min), respectively, had no significant effects on omasal myoelectrical activity. The i.v. administration for 15 min of alpha 1- or alpha 2-agonists phenylephrine (4 micrograms/kg/min) or naphazoline (2.5 micrograms/kg/min), respectively, increased the frequency and the amplitude of groups of myoelectrical discharges of omasum, as well as the duration of its activity. Pretreatment of animals with prazosin blocked the responses to phenylephrine. Yohimbine prevented the effects of naphazoline dose-dependently. It is suggested that both alpha 1- and alpha 2-adrenoreceptors are involved in regulation of the sheep's omasal notility. This regulation did not seem to be a simple consequence of the changes in the reticular motility.     

Pharmacokinetics of pentobarbital and thiamylal as combined anesthetics in sheep

This study was performed to investigate the possible mechanisms underlying prolongation of anesthesia times in sheep caused by the sequential administration of thiamylal and pentobarbital. Sodium thiamylal was injected as an intravenous bolus dose (13.2 mg/kg) followed in 7 min by sodium pentobarbital (14.3 mg/kg) by the same route to seven sheep. Separate studies were conducted for each of the two drugs administered separately to the same animals at the same doses. Mean anesthesia times (to the return of the palpebral reflex) were 7.89 min (thiamylal), 5.39 min (pentobarbital) and 34.1 min (the sequential combination). The kinetic parameters Vd(area), Vd(ss), t 1/2 beta, and ClB for either drug were not affected by the other when given in combination. The t 1/2 alpha was shorter, and the Vc was smaller, for pentobarbital when administered with thiamylal, while there were no changes in thiamylal disposition for the combination regimen. Computer-generated curves, associated with the two-compartment open model showing the fraction of dose in each compartment as a function of time, illustrated that pentobarbital rapidly achieved higher concentrations in the peripheral compartment after prior thiamylal administration. Protein-binding studies showed that this could not be attributed to displacement of pentobarbital from plasma albumin by thiamylal. Calculation of total and free drug concentrations at the time of awakening showed that, when the drugs were combined, the concentration of each drug was less than half of that observed at awakening when they were studied separately. It can be concluded that the prolonged sleeping times associated with the sequential combination of the two agents were not due to an alteration in kinetic parameters of either drug caused by the other, but rather to an additive effect of the subanesthetic concentrations of the two drugs when combined. The fact that sleeping times were supra-additive is attributed to a shift of awakening time from the distribution (alpha) phase, when given independently, to the elimination (beta) phase when administered in combination.     

Further studies on the antinociceptive activity and respiratory effects of buprenorphine in sheep

The thermal and mechanical analgesic profile of buprenorphine at a dose rate of 1.5 micrograms/kg i.v. was investigated in five sheep. This dose produced significant analgesia for 40 min against the thermal stimulus, but no mechanical antinociception. A higher dose rate of 12 micrograms/kg also failed to produce antinociception to a mechanical stimulus. In addition, the effect of the drug (6 micrograms/kg) on respiratory gas tensions was determined and no significant changes were observed.     

A comparison of the sedative effects of three α2-adrenoceptor agonists (romifidine, detomidine and xylazine) in the horse

The sedative effects of a new alpha 2-adrenoceptor agonist, romifidine, were compared with those of xylazine and detomidine. Five horses were treated with two doses of romifidine (40 micrograms/kg body weight and 80 micrograms/kg body weight), two doses of detomidine (10 micrograms/kg body weight and 20 micrograms/kg body weight) and one dose of xylazine (1 mg/kg body weight) given by intravenous injection using a Latin-square design. The dose of 80 micrograms/kg romifidine appeared equipotent to 1 mg/kg xylazine and 20 micrograms/kg detomidine, although at these doses both xylazine and detomidine had a shorter action. Detomidine 20 micrograms/kg and xylazine both produced greater lowering of the head and a greater degree of ataxia than romifidine at either dose. Romifidine produced sedation similar to that of the other drug regimes. The effect upon imposed stimuli was similar.     

Effect of intracerebroventricular orexin-B on food intake in sheep.

Orexin is a hypothalamic neuropeptide that regulates feeding behavior in rats. Orexin-B has recently been cloned in pigs and was shown to stimulate food intake after intramuscular injection. This study was designed to determine whether intracerebroventricular (ICV) and intravenous injections of orexin could regulate appetite in sheep. Suffolk wethers were moved to indoor facilities, adapted to diets for 6 wk, and trained to stand in stanchions for 3 to 6 h each day for 2 wk before indwelling ICV cannulas were installed. These sheep were provided water and they consumed feed ad libitum. On the day before an experiment, each sheep was cannulated in a jugular vein. On the day of an experiment, sheep were placed in stanchions and allowed to stand for 1 h before use. Sheep were then monitored over a 2-h control period before i.v. injection with saline or porcine orexin-B (3 micrograms/kg BW) or ICV injection with artificial cerebrospinal fluid (CSF), orexin (0.03, 0.3, or 3 micrograms/kg BW) or in a second experiment with either orexin B (0.03, 0.3, 3 micrograms/kg BW), neuropeptide-Y (NPY; 0.3 microgram/kg BW), or orexin plus NPY. Food intake was monitored for consecutive 2-h periods. The i.v. injections of orexin did not affect food intake or metabolite or hormone concentrations. In ICV sheep, orexin increased food intake at 2 (P < 0.04) and at 4 h (P < 0.02). Food intake was greatest with the 0.3 microgram/kg BW dosage of orexin (P < 0.05). In the first 2 h after injection, orexin had an effect similar to that of NPY (0.23 kg for orexin and 0.2 kg for NPY). The combination of NPY and orexin had a greater effect on food intake (to 0.34 kg) than did either orexin (P < 0.05) or NPY (P < 0.008) alone. Differences were not apparent in the subsequent 2-h interval. No differences were noted in free fatty acid, glucose, growth hormone, luteinizing hormone, or insulin concentrations following orexin injection. There was an effect of ICV orexin treatment on plasma cortisol concentrations (P < 0.002). Cortisol was increased by orexin at the 0- to 2-h (P < 0.008) and in the 2- to 4-h (P < 0.009) intervals after orexin injection. These data indicate that central administration of orexin stimulates feed intake in sheep.     

Relationships between metabolic changes and clinical signs in pregnant sheep given endotoxin.

Groups of four pregnant ewes were allocated to the following feeding and intravenous endotoxin treatments: fed, Escherichia coli endotoxin (50 micrograms/kg X 75), fed, saline, fasted, E. coli endotoxin (50 micrograms/kg X 75) and fasted, saline. Endotoxin administration resulted in depression, fever, hypoglycemia, hypocalcemia and a reduction in nonesterified fatty acid and ketone body concentrations. Depression correlated best with body temperature (r = 0.76), fasted sheep showed smaller increases in body temperature and were less depressed following endotoxin. Three of eight endotoxin treated sheep died, mortality was not related to rectal temperature but was associated with lactic acidosis. Hypoglycemia was not associated with either death or depression. Fed sheep that were unable to stand had lower serum calcium concentrations than standing sheep.     

Central and peripheral α-adrenoceptor actions of amitraz in the dog

The aim of this study was to determine the contribution of alpha 2- and alpha 1-adrenoceptor agonist activity of the formamidine, amitraz, on peripheral circulation in the dog. Intra-arterial injections of amitraz (0.25-5.0 micrograms/kg) produced a dose-dependent increase in perfusion pressure in the autoperfused hind limbs of methoxyflurane-anaesthetized dogs. A constant blood flow to the hind limbs was maintained using a peristaltic pump. Intravenous phentolamine (0.5 mg/kg), prazosin (35 micrograms/kg) and yohimbine (10 micrograms/kg) in separate experiments antagonized the vasoconstrictor actions of amitraz and produced a parallel shift to the right of the amitraz dose-response curve. Cumulative doses of amitraz (0.5-15 micrograms/kg) given by intracisterna magna (i.c.m.) injections reduced mean arterial pressure and heart rate in a dose-dependent manner. Similar responses were produced by intravenous amitraz but at much higher doses. In separate experiments amitraz-induced hypotension (doses up to 25 micrograms/kg i.c.m.) was prevented by pre-treatment with yohimbine (30 micrograms/kg i.c.m.) but not prazosin (20 micrograms/kg i.c.m.). Both antagonists partially inhibited the bradycardia produced by amitraz. It is concluded that amitraz stimulates alpha 1- and alpha 2-adrenoceptors to produce vascular constriction. The central hypotensive action of amitraz appears to be mediated by alpha 2-adrenoceptors; however, both receptor subtypes appear to be stimulated to produce bradycardia.     

Ibuprofen prevents Pasteurella hemolytica endotoxin-induced changes in plasma prostanoids and serotonin, and fever in sheep

Intravenous infusion of Pasteurella hemolytica endotoxin caused marked increases in the plasma levels of thromboxane B2 (TxB2), prostaglandins (PG) and serotonin in sheep. The control values for TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin before endotoxin infusion averaged 283 +/- 53 (standard error of mean), 281 +/- 14 and 199 +/- 27 pg/ml and 57 +/- 3 ng/ml, respectively. At 50 min during endotoxin infusion, these values were increased to their maximum of 376, 339, 325 and 202% of control, respectively. Body temperature increased from the control value of 39.5 +/- 0.1 degrees C to a maximum of 41.5 +/- 0.1 degrees C at 200-300 min of infusion. In the second part of this study, we have examined the effects of ibuprofen on endotoxin-induced increases in plasma PG, TxB2, and serotonin levels and body temperature. The control values for TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and temperature prior to ibuprofen and endotoxin infusion averaged 238 +/- 35, 335 +/- 44 and 248 +/- 28 pg/ml, 65 +/- 3 ng/ml and 40.1 +/- 0.2 degrees C, respectively. A loading dose (15 mg/kg) of ibuprofen was followed by infusion of endotoxin (12 micrograms/kg) and ibuprofen (43.3 mg/kg) over 500 min. Plasma levels of 6-keto-PGF1 alpha and serotonin increased only to 131 and 149% of control at 50 min of infusion, and levels of PGF2 alpha and TxB2 decreased to 50 and 80% of control at 100 and 150 min of infusion, respectively. Temperature remained unchanged. Ibuprofen effectively suppressed endotoxin-induced increases in the plasma levels of TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin and body temperature. It was concluded from the present study that nonsteroidal anti-inflammatory drugs as an adjunct to antibiotic therapy might have a rational basis in treatment of endotoxin toxicity.     

Vagal afferent activities and respiratory reflexes during drug-induced bronchoconstriction in the guinea pig.

Vagal afferent activities and respiratory reflexes during drug-induced bronchoconstriction were studied in 31 anesthetized, spontaneously breathing or artificially ventilated guinea pigs. Histamine (5, 10, 20 micrograms/kg), ACh (10, 20, 40 micrograms/kg) and endothelin-1 (2 micrograms/kg) were intravenously injected to the animals in order to induce the bronchoconstriction. In spontaneously breathing and vagi intact animals, a considerable respiratory change characterized by rapid-shallow breathing was elicited by histamine. Such respiratory change was abolished by bilateral vagotomy, indicating that the vagal pathway fairly participated in the respiratory change during bronchoconstriction. Indeed, recordings of electrical activities of single vagal afferent nerve fibers from pulmonary stretch and irritant receptors elucidated that the bronchoconstriction by the three drugs markedly influenced these receptor activities. The response of stretch receptors to bronchoconstriction was grouped into four types: two of those types showed a marked increase in their activities and the other two a decrease or no change. Such uneven response was assumed to be derived from heterogenous contraction and aeration among the intrapulmonary small airway. On the other hand, irritant receptors were invariably stimulated by increased transmural pressure during bronchoconstriction. Administration of isoproterenol (20 micrograms/kg) which inhibited the smooth muscle contraction abolished stimulatory effect of the drugs to irritant receptors, suggesting that the effect was due to indirect action through the muscle contraction rather than their direct action to the nerve endings.     

Comparison of serum and renal gentamicin concentrations with fractional urinary excretion tests as indicators of nephrotoxicity

Gentamicin was given to six sheep at a dosage rate of 80 mg/kg/day divided into three daily doses to cause nephrotoxicity. Peak serum gentamicin concentrations rose significantly throughout dosing (P less than 0.05), but trough serum gentamicin concentrations increased dramatically (P less than 0.01) from initial concentrations of 3.2-9.1 micrograms/ml to final trough concentrations of 31.5-195 micrograms/ml by 6-10 days on gentamicin. The serum gentamicin elimination half-life (t1/2) was doubled in each animal by approximately 6 days on therapy, with the sheep that were the most clinically affected by the nephrotoxic effects of gentamicin showing increases in t1/2 earlier than those sheep that remained less intoxicated. These changes occurred before many other clinical indicators of nephrotoxicity, with only urinary enzyme excretions preceding the changes in gentamicin elimination. Thus, alterations in the elimination of gentamicin may be one of the first clinical indicators of the occurrence of gentamicin-induced nephrotoxicity.     

Central and peripheral serotonergic control of forestomach motility in sheep

Participation of tryptaminergic receptors in the control of forestomach motility was investigated in conscious sheep using strain-gauges and chronically implanted electrodes. Two hours after feeding the sheep, serotonin (5-HT) was infused into the jugular vein (i.v.), or the carotid artery (i.c.), or into the lateral cerebral ventricles (i.c.v.), over a 10-min period. An i.v. dose of 16 micrograms/kg/min abolished the cyclic propagated contractions throughout the forestomach, increased ruminoreticular tone, and induced simultaneous contractions of all the parts of the rumen. A dose of 1.6 micrograms/kg/min i.c. or i.v. 5-HT inhibited phasic contractions. The effects of 5-HT were blocked completely by i.c.v. administration of methysergide (20 micrograms/kg) and imipramine (200 micrograms/kg), and blocked partially by naloxone (25 micrograms/kg), but unaffected by atropine (50 micrograms/kg). The inhibitory effects of i.v. 5-HT were antagonized by methysergide (200 micrograms/kg, i.v.) but unaffected by imipramine (2 mg/kg, i.v.) and atropine (250 micrograms/kg, i.v.). Only the i.v. administration of methysergide blocked the inhibition induced by i.c. infusion (1.6 micrograms/kg/min) of 5-HT. It is suggested that 5-HT exhibits an inhibitory control on forestomach phasic contractions through hypothalamic and bulbar 5-HT receptors, and exerts peripheral excitatory effects on the tone of the rumen wall.