Dexmedetomidine alleviates ethanol withdrawal symptoms in the rat

The effect of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on ethanol withdrawal symptoms was studied in chronically ethanol-fed rats. After a 4-day ethanol intoxication period the rats were given s.c. injections of dexmedetomidine (3, 10, or 30 micrograms/kg) or saline (control group) at 10, 16, 22, and 39 h after the last dose of ethanol. The severity of ethanol withdrawal symptoms (rigidity, tremor, irritability, hypoactivity) was rated up to 58 h, blind to the treatments. The results showed that dexmedetomidine at doses 10 and 30 micrograms/kg significantly diminished the severity of the ethanol withdrawal reaction as measured by the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability). Dexmedetomidine at 10 micrograms/kg was the most effective dose, especially in the latter half of the withdrawal period (23-58 h after last dose of ethanol). The results suggest that dexmedetomidine in the treatment of ethanol withdrawal symptoms should be further studied.     

Corticosterone increases severity of acute withdrawal from ethanol, pentobarbital, and diazepam in mice

It has been suggested that withdrawal from several subclasses of central nervous system (CNS) depressants involves common underlying mechanisms. For example, mice genetically selected for severe ethanol withdrawal convulsions (Withdrawal Seizure Prone or WSP) have also been found to express severe withdrawal following treatment with barbiturates and benzodiazepines. Corticosteroids appear to modulate severity of withdrawal from CNS depressants. Therefore, it was hypothesized that corticosterone would enhance withdrawal convulsions following acute ethanol, pentobarbital, and diazepam in WSP mice. Corticosterone (20 mg/kg) administered following each of these drugs significantly increased severity of handling-induced convulsions during withdrawal. Corticosterone did not affect pre-withdrawal convulsion scores or handling-induced convulsions of drug-naive mice. These results suggest that withdrawal convulsions following acute ethanol, pentobarbital, and diazepam are sensitive to modulation by corticosterone and they support the hypothesis that stress may increase drug withdrawal severity.     

Contingent tolerance, compensatory responses, and physical dependence in diazepam-treated amygdala-kindled rats

Three groups of amygdala-kindled rats received 10 bidaily treatment trials: On each trial, the drug-before group received a diazepam (2.5 mg/kg i.p.) injection 1 hr before a convulsive stimulation, the drug-after group received a diazepam injection 1 hr after a stimulation, and the vehicle control group received a vehicle injection either 1 hr before or 1 hr after a stimulation. After treatment, only the drug-before group displayed significantly longer forelimb clonus under the influence of diazepam (that is, they displayed contingent tolerance to diazepam's anticonvulsant effect) and significantly longer forelimb clonus while drug free. Following a 14-day retention period, the rats in the drug-before group retained significant levels of contingent tolerance but did not display significant increases when tested drug free. These data suggest that compensatory responses do not play a causal role in the expression of contingent tolerance.     

Serotonin reuptake inhibitor withdrawal

We studied reported withdrawal symptoms in a retrospective chart review of 352 patients treated in an outpatient clinic with the nonselective serotonin reuptake inhibitor clomipramine or with one of the selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, or sertraline. In 171 patients who were supervised during medication tapering and discontinuation, the most common symptoms were dizziness, lethargy, paresthesia, nausea, vivid dreams, irritability, and lowered mood. When patients with at least one qualitatively new symptom were defined as cases, these symptoms occurred significantly more frequently in patients who had been treated either with one of the shorter half-life SSRIs, fluvoxamine or paroxetine (17.2%), or with clomipramine (30.8%), than in patients taking one of the SSRIs with longer half-life metabolites, sertraline or fluoxetine (1.5%). The rate was not significantly different between the different shorter half-life treatments. Cases treated with fluvoxamine or paroxetine had received a significantly longer period of treatment (median 28 weeks) than noncases (16 weeks), but there were no significant associations with age or with diagnostic grouping. There was a trend toward an association with male sex. The majority of cases occurred despite slowly tapered withdrawal. Symptoms persisted for up to 21 days (mean = 11.8 days) after onset. These symptoms were relieved within 24 hours by restarting the medication, but were not relieved by benzodiazepines or by moclobemide. A role has been suggested for serotonin in coordinating sensory and autonomic function with motor activity. We suggest that this may lead to useful hypotheses about the pathophysiology of withdrawal symptoms from serotonin reuptake inhibitors.     

Effect of an ascending dose regimen on the development of tolerance to the anticonvulsant effect of diazepam.

Assessed the effect of an ascending dose regimen on the development of tolerance to diazepam's anticonvulsant effect. During the 22 trials of the tolerance development phase, 55 adult male, amygdala-kindled rats received either a series of dosage injections ranging from high (10 mg/kg), to low (1 mg/kg), and ascending (1 mg/kg and increased by 0.2-mg/kg increments to 3 mg/kg) or saline injections. Diazepam was administered by intraperitoneal/ly (ip) injection once every 48 hrs, and each injection was followed 1 hr later by a convulsive stimulation. The ascending dose rats displayed significantly more tolerance to the anticonvulsant effect of diazepam than did the high dose, low dose, or saline rats. By contrast, both the ascending and high dose rats displayed a significant withdrawal effect (i.e., increased duration of convulsions) after the cessation of diazepam injections. Results demonstrate that administration of ascending dosages can facilitate the development of tolerance to anticonvulsant drug effects and that tolerance and withdrawal are not necessarily inextricably related. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Elantrine in the treatment of parkinsonism

A new drug, elantrine, blocks the tremorogenic effect of exotremorine, nicotine and harmine in animals. A double blind study compared elantrine with trinhexyphenidyl and against a baseline placebo period, in a group of Parkinson patients. Both, elantrine and trihexyphenidyl treatment, reduced tremor scores at the conclusion of the respective treatment periods, but closer analysis revealed 65% of patients receiving elantrine had lower tremor scores compared to their baseline (placebo) opposed to only 53% receiving trihexyphenidyl. Both drugs produced aequal effect on rigidity. Another group of Parkinson patients receiving clinically optimal doses of L-dopa were treated with either elantrine or placebo, in blind fashion. Analysis of both tremor and rigidity revealed mean scores significantly lower (P less than 0.05) for those patients receiving elantrine than placebo. Also, there was a statistically significant difference in average total symptom scores favoring the elantrine group. Significant improvement with elantrine administration began after the second week for rigidity and after the third week for tremor. Elantrine is a safe, well tolerated agent which is effective alone in the treatment of parkinsonism but significantly enhances the effectiveness of L-dopa, particularly with respect to tremor and rigidity.     

Behavioral assessment of neuroleptics (3)--Schizophrenia negative symptoms-like model induced by PCP

Immobility induced by forced swimming is well known as an animal model of depression. To develop an animal model for the negative symptoms of schizophrenia, in particular, the depressive symptoms, the effect of phencyclidine (PCP) on immobility in the forced swimming test was investigated in mice, since PCP produces negative symptoms-like behavioral changes in humans. Repeated treatment with PCP (10 mg/kg/day, sc, once a day for 14 days) prolonged the immobility time in the forced swimming test 24 hr after the final injection compared with saline treatment; the effect was not obtained by single treatment with PCP (10 mg/kg), or by repeated treatment with methamphetamine (0.3 and 1 mg/kg/day, sc, once a day for 14 days). The enhancing effect of PCP on the immobility persisted for at least 21 days after the withdrawal of the drug. Desipramine (10 mg/kg, po) attenuated the immobility induced by the forced swimming in mice repeatedly treated with saline. The enhancing effect of PCP on the immobility was attenuated by risperidone (0.3 mg/kg), clozapine (3 and 10 mg/kg), and desipramine (20 and 50 mg/kg), whereas haloperidol (0.3 and 1 mg/kg) had no effect. These results suggest that the enhancement of immobility in the forced swimming test brought about by repeated PCP treatment could be used as a model of the negative symptoms, particularly the depression, of schizophrenia.     

Acute liver failure following tetrabamate

Tetrabamate (Atrium), a composite preparation of phenobarbital, difebarbamate and febarbamate, is widely used to reduce ethanol withdrawal symptoms such as tremor, agitation and anxiety. Generally this drug is well tolerated and a few cases of reversible hepatitis as well as clinically mild symptoms of asthenia have been described. We report on a 28-year-old female patient admitted to hospital with acute liver failure after treatment with tetrabamate because of alcohol withdrawal symptoms. Liver biopsy revealed a drug-induced toxic alteration with extensive panlobular necrosis without signs of alcoholic hepatitis. Under supportive therapy liver parameters normalized in 3 months. In view of this potentially lethal adverse effect of tetrabamate, it should not be used for ethanol withdrawal symptoms.     

The novel anticonvulsant, gabapentin, protects against both convulsant and anxiogenic aspects of the ethanol withdrawal syndrome

The effects of the anticonvulsant, gabapentin, were investigated, in mice, on the withdrawal convulsive behaviour and anxiety-related behaviour that are produced by cessation of prolonged intake of ethanol. When given at 50 or 100 mg/kg, this compound decreased the rise in handling-induced hyperexcitability which occurs during the withdrawal period; the effects were most pronounced for the first 4 hr after administration. Gabapentin also decreased the convulsive response to an audiogenic stimulus during the withdrawal period. The elevated plus-maze, with both traditional and ethological indices of activity was used as a test of anxiety-related behaviour after cessation of chronic ethanol treatment. Gabapentin, at 50 and 100 mg/kg, was found to decrease some, although not all, of the signs of withdrawal-induced anxiety. At doses up to and including 200 mg/kg, gabapentin had no effect on motor co-ordination or spontaneous locomotor activity in control animals. The results demonstrated that gabapentin has a selective action in decreasing both convulsive and anxiety-related aspects of withdrawal behaviour after chronic ethanol treatment. It is possible that further studies with this compound may shed further light on the mechanisms involved in the withdrawal syndrome.     

Gender and the effects of different doses of nicotine gum on tobacco withdrawal symptoms.

Women and men were compared on the extent to which 2-mg (n?=?40), 4-mg (n?=?41), and 4-mg then 2-mg (n?=?47) nicotine gum prescribed over an 8-week period relieved cigarette withdrawal symptoms. Gender differences for nicotine gum withdrawal symptoms across doses were also examined. Results showed that women assigned to 2-mg nicotine gum experienced more severe cigarette withdrawal symptoms than those assigned to the other gum conditions. In general, no differences for nicotine gum dose in relieving cigarette withdrawal symptoms were observed in men. Women experienced more severe cigarette withdrawal symptoms than men, predominantly in the 2-mg nicotine gum condition. Women also experienced greater withdrawal symptoms from nicotine gum compared with men. For both genders, those assigned to the 4-mg nicotine gum group throughout treatment experienced more severe nicotine gum withdrawal than those assigned to the other nicotine gum conditions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Running and addiction: Precipitated withdrawal in a rat model of activity-based anorexia.

Exercise improves cardiovascular health, strengthens muscles and bones, stimulates neuroplasticity, and promotes feelings of well-being. However, when taken to extremes, exercise can develop into an addictive-like behavior. To assess the addictive potential of exercise, withdrawal symptoms following injections of 1.0 mg/kg naloxone were compared in active and inactive male and female rats. Active and inactive rats were given food for 1 hr or 24 hr/day. Additionally, a group of inactive rats was pair-fed the amount of food consumed on the previous day by food-restricted active rats. Rats fed for 1 hr/day decreased food intake and lost weight. Additionally, food-restricted active rats increased wheel running. There was a direct relationship between the intensity of running and the severity of withdrawal symptoms. Active food-restricted rats displayed the most withdrawal symptoms, followed by active rats given 24-hr access to food. Only minimal withdrawal symptoms were observed in inactive rats. These findings support the hypothesis that exercise-induced increases in endogenous opioid peptides act in a manner similar to chronic administration of opiate drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adipose tissue omega-3 and omega-6 fatty acid content and breast cancer in the EURAMIC study. European Community Multicenter Study on Antioxidants, Myocardial Infarction, and Breast Cancer

Three experiments examined the effect of either withdrawal from diazepam, or repeated treatment with the convulsant, pentylenetetrazol (PTZ), on behaviour and seizure threshold. The behaviours measured were on the elevated plus maze and in the four-plate test; seizure threshold was measured as dose of PTZ infused via the tail vein to the first clonic twitch. In experiment 1, we examined the effect of either single or repeated withdrawal from diazepam using a procedure in which the drug was administered SC in a slow release depot. Three cycles of withdrawal from diazepam were compared to a single withdrawal experience. A single withdrawal from diazepam following chronic treatment gave rise, 72 h following the last dosing, to behavioural changes, suggestive of anxiety, in both tests, but did not result in a reduced convulsant threshold. In contrast, repeated withdrawal resulted in a reduction in sensitivity in several measures of anxiety, but sensitised the mice to the convulsive effects of the PTZ. The unexpected failure to find an increased sensitivity to a convulsive agent following a single withdrawal from SC diazepam was examined in experiment 2. The seizure threshold following a single withdrawal of mice which had received diazepam chronically IP in aqueous vehicle was significantly reduced relative to vehicle-treated controls, whereas that of animals receiving the same dose SC in oil, was not. It is argued that the difference may arise from the animals treated repeatedly with IP diazepam unintentionally experiencing repeated withdrawal, since the half-life of the drug by this route is short. In experiment 3, repeated sub-convulsant PTZ treatment reduced the convulsant threshold (the dose of PTZ required to give rise to the first clonic twitch), but had no significant effect on the behavioural measures of anxiety compared to a single dose of PTZ or vehicle controls. The results suggest that repeated withdrawal from chronic treatments with diazepam sensitises mice to convulsant stimuli in a manner resembling the effects of repeated administration of sub-convulsant doses of PTZ, but that neither repeated PTZ nor repeated diazepam withdrawal results in increased sensitivity to anxiogenic stimuli; rather, repeated withdrawal from diazepam may reduce the susceptibility of mice to behavioural measures of anxiety.     

A problem with the interpretation of before-and-after experiments of drug tolerance.

Four groups of amygdala-kindled rats were exposed lo 15 daily tolerance-development trials. On each trial, 1 group received diazepam (2.5 mg/kg IP) 1 hr before a convulsive stimulation, 1 group received diazepam 1 hr after a stimulation, 1 group received 15 diazepam injections but no stimulation, and a combined control group received 15 vehicle injections either with or without a stimulation. Consistent with previous findings, only subjects that had received diazepam before the stimulations during the tolerance-development phase displayed significant tolerance to diazepam's anticonvulsant effect on the first test trial. The major new finding was that diazepam injections by themselves induced significant savings (i.e., residual tolerance) on the test trials but that diazopam injections preceded by convulsive stimulations did not. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased bone marrow uptake on Tc-99m DMSA scintigraphy in a patient with renal osteodystrophy

Anxiogenic action of m-chlorophenylpiperazine (mCPP), a 5-HT1C receptor agonist, was studied in naive rats and in ethanol-tolerant rats following withdrawal from chronic ethanol administration. The purpose of this investigation was to determine whether a sensitization to mCPP develops during withdrawal from chronic ethanol. Male Long-Evans hooded rats were fed a liquid diet containing 4.5% ethanol or dextrin (as control) for four days. Twelve hours (acute withdrawal) or 4 days (protracted withdrawal) after the last dose of ethanol, rats were injected with saline or mCPP (0.08-5.0 mg/kg) and were tested in the elevated plus-maze 15 min postinjection. A reduction in percent open-arm activity, indicative of anxiogenic behavior, was observed in ethanol-treated rats injected with saline. Administration of mCPP further reduced the percent open-arm entries and time in ethanol-withdrawn rats. An eightfold reduction in maximum effective dose of mCPP was observed during acute ethanol withdrawal as compared to that in naive rats. During protracted ethanol withdrawal the maximum effective dose of mCPP was reduced by 75%. A shift of the mCPP dose-response curve to the left following withdrawal from chronic ethanol may indicate that 5-HT1C receptor sites are more sensitive to the activation by an agonist. This effect may be exploited in developing specific 5-HT1C receptor antagonists for the treatment of ethanol withdrawal symptoms.     

Agreement of mutational characteristics of heterocyclic amines in lacI of the Big Blue mouse with those in tumor related genes in rodents

Focal cerebral ischemia was induced in a rat model of middle cerebral artery occlusion. Three groups of adult male Sprague-Dawley rats, given food and water ad libitum, were subjected to 4 hr of middle cerebral artery occlusion. All were given vehicle control and ethanol pretreatments intraperitoneally 1 hr before. Mean ipsilateral brain water content in the control, 2 g/kg ethanol, and 2 g/kg ethanol + insulin-treated groups showed: ischemia core: 81.1%, 82.5%, and 80.9%; intermediate zone: 81.0%, and 80.3%; and outer zone: 80.3%, 81.3%, and 80.1%, respectively. Brain Na+ and K4 content in these groups paralleled the water content. In addition to significantly (p < 0.05) more brain edema, the 2 g/kg ethanol-treated animal group also had significant hyperglycemia. In contrast, the 2 g/kg ethanol + insulin-treated animals were normoglycemic and had ischemic, intermediate, and outer zone Na+, K+, and Cl- levels comparable with the control group (p > 0.05). These results stress the importance of measuring and controlling plasma glucose levels in the in vivo studies of the neurotoxic effects of acute ethanol.     

Effects of N-methyl-D-aspartate receptor antagonists on discriminative stimulus effects of naloxone in morphine-dependent rats using the Y-maze drug discrimination paradigm

The present study assessed the ability of various site-selective N-methyl-D-aspartate (NMDA) receptor antagonists to affect the discriminative stimulus properties of naloxone in morphine-dependent rats. Adult male Wistar rats were trained to discriminate 0.1 mg/kg of s.c. naloxone from saline using a Y-maze shock-avoidance procedure. Naloxone-appropriate responding was exhibited as a function of naloxone dose (0.01-1.0 mg/kg, ED50 = 0.03 mg/kg) and was also observed when morphine treatment temporarily was discontinued (8-96 hr, peak at 24 hr). Discriminative stimulus effects of naloxone (0.1-3.0 mg/kg) were antagonized by morphine (10-100 mg/kg). Ligands of peripheral opioid receptors failed to either substitute for naloxone (methylnaloxone, 0.1-3.0 mg/kg) or attenuate naloxone's stimulus effects (loperamide, 1-30 mg/kg). In rats treated with the training dose of naloxone, administration of dizocilpine (0.03-0.3 mg/kg) and D-CPPene (1-10 mg/kg) decreased levels of naloxone-appropriate responding, whereas memantine (1-30 mg/kg), ACEA-1021 (10 and 50 mg/kg) and eliprodil (3-30 mg/kg) seemed to have little or no effects. Meanwhile, all NMDA receptor antagonists produced a decrease in the occurrence of two or more of the following opioid withdrawal signs: weight loss, forelimb tremor, ptosis, diarrhea and "wet-dog"-like shaking. Additionally, dizocilpine (0.1 mg/kg), D-CPPene (5.6 mg/kg) and ACEA-1021 (50 mg/kg) but not memantine (10 mg/kg) or eliprodil (30 mg/kg) significantly reduced the naloxone-appropriate escape area selection when administered during the period of suspended morphine treatment 24 hr after the last morphine injection. Thus, NMDA receptor antagonists appear to inhibit the discriminative stimulus effects of both naloxone-precipitated and spontaneous morphine withdrawal, and this ability depends on the type of antagonist applied.     

Blood sampled in rats from right ventricle may not always be truly representative of a mixed venous sample

The efficacy of the diazepam loading dose method of treatment of delirium tremens was assessed in comparison with the traditional therapy. The experimental group and the control group comprised 51 and 45 patients respectively. The clinical institute withdrawal assessment for alcohol (CIWA-A) scale was applied to assess the intensity of the symptoms. Diazepam doses in the experimental group oscillated from 40 to 210 mg (mean 86.9 +/- 47.2 mg). The control group was receiving diazepam and other psychotropic drugs in divided doses. In the experimental group deliric symptoms were present from 2 to 24 h (mean 6.9 +/- 4.8 h), and in the control group from 2 to 123 h (mean 33.8 +/- 25.7 h). The results show a large efficacy of the loading dose method corresponding to substantial reduction of the psychosis duration (fivefold in comparison to the control group). The method proved to be safe, with no significant complications.     

Protracted treatment with diazepam reduces benzodiazepine1 receptor-mediated potentiation of gamma-aminobutyric acid-induced currents in dissociated rat hippocampal neurons

Tolerance to benzodiazepines (BZs) is thought to involve alterations of the gamma-aminobutyric acid (GABA)A receptor as a result of the prolonged occupancy of its modulatory BZ recognition site. We used the whole-cell patch-clamp technique to compare the functional and pharmacological properties of GABAA receptors in acutely dissociated hippocampal neurons from the control or diazepam-tolerant rats. Administration of diazepam (15 mg/kg p.o.) twice a day for 10 days induced tolerance as demonstrated by the decreased potency of acute diazepam i.p. injections to protect against pentylenetetrazole-induced clonictonic convulsions (10.5% of tolerant rats protected by 0.1 mg/kg of diazepam against 55% of nontreated rats, 48 hr after the last dose of the chronic treatment). The specific current induced by 1 microM GABA in acutely dissociated hippocampal neurons 48 hr after withdrawal (10.5 +/- 1.3 microA/cm2) was similar to that observed in the control rats (8.7 +/- 0.8 microA/cm2). The EC50 value for GABA was unchanged by the chronic treatment [6.3 (5.4-7.1) and 7.5 (6.2-8.7) microM in neurons from the control and treated rats, respectively]. The potency of the nonselective allosteric modulator diazepam to stimulate Cl- currents was identical in cells from treated rats [EC50 values of 25 (20-30) and 34 (26-41) nM in the control and treated rats, respectively; P < .05], but the potency of the selective BZ1-site ligand zolpidem was decreased [EC50 values of 99 (88-111) and 267 (221-313) nM in the control and treated rats, respectively; P < .05]. The maximal potentiation of the GABA-induced current was significantly decreased with diazepam (maximal potentiation: 168.0 +/- 16.2 and 124.0 +/- 8.9% in the control and treated rats, respectively). These results suggest that tolerance to diazepam is accompanied in hippocampal neurons by a decrease in BZ1 binding sites and in the functional coupling of BZ/GABA recognition sites.     

Chronic ethanol inhibits inositol metabolism in specific brain regions

Many neurotransmitters and hormones in the nervous system transmit signals through receptors coupled to the poly-phosphoinositide (PI) signaling pathway. In this study, an in vivo protocol with [3H]inositol was used to examine the effect of chronic ethanol administration on inositol metabolism and poly-PI turnover in the cerebral cortex, hippocampus, and cerebellum of mouse brain. C57BL/6 mice were given a nutritionally complete liquid diet containing either ethanol (5%, w/v) or isocaloric sucrose for 2 months. Mice were injected intracerebrally with [3H]inositol; after 16 or 24 hr, they were injected intraperitoneally with lithium (8 mEq/kg body weight) to inhibit the inositol monophosphatase (IP1) activity. All mice were decapitated 4 hr after lithium injection. Labeled inositol phospholipids accounted for 16 to 23% of total labeled inositol in different regions of control mouse brain, and the percentages in the hippocampus were consistently higher than the cerebral cortex and cerebellum. In control mice, the percentages of labeled IP1 after a 4-hr lithium treatment were 11.5%, 9.9%, and 3.7% for cerebral cortex, hippocampus, and cerebellum, respectively. Chronic ethanol feeding resulted in a significant (p < 0.05) decrease in the percent of labeled IP1 and inositol phospholipids, and this effect was observed in the cerebral cortex and, to a lesser extent, hippocampus but not cerebellum. When ratios of labeled IP1 were expressed against labeled inositol phospholipids as an index of the poly-PI turnover activity, significant decreases in IP/lipid ratios were observed in the cerebral cortex, but not the hippocampus or cerebellum. Although mice killed 24 + 4 hr after the last ethanol feeding would have experienced an 8-hr period of ethanol withdrawal, compared with the 16 + 4-hr group, no differences in IP/lipid ratios were observed between the two time groups. These results illustrate regional differences in the effect of chronic ethanol on inositol metabolism in the brain, but no difference in poly-PI turnover in brain due to ethanol withdrawal.     

Effects of clonidine, dexmedetomidine and xylazine on thermal antinociception in rhesus monkeys

The antinociceptive effects of the s.c. administration of the alpha-2 agonists clonidine (0.0032-1.0 mg/kg), dexmedetomidine (0.001-0.032 mg/kg) and xylazine (0.1-3.2 mg/kg) were examined in the warm-water tail withdrawal assay in rhesus monkeys. The three agonists were dose-dependently effective in this assay; their potency order being dexmedetomidine > clonidine > xylazine. The alpha-2 antagonist idazoxan (0.1-3.2 mg/kg) caused dose-dependent and roughly parallel rightward shifts in the dose-effect curves for the three agonists. Apparent pA2 analysis with idazoxan yielded homogeneous values for the three agonists, supporting the notion that similar receptors mediate their antinociceptive effects. The opioid antagonist quadazocine (1.0 mg/kg) did not antagonize the antinociceptive effects of clonidine and xylazine, indicating that opioid receptors do not participate in the effects of the compounds in this assay. At dose ranges found to be effective in the antinociceptive assay, clonidine, dexmedetomidine and xylazine also dose-dependently caused sedation, muscle relaxation, bradycardia and moderate respiratory depression. The sedative, muscle relaxant and respiratory depressant effects of xylazine could be antagonized by idazoxan, suggesting that these effects may be mediated through alpha-2 receptors. These data indicate that the three imidazoline alpha-2 agonists, clonidine, dexmedetomidine and xylazine are effective s.c. in the warm-water tail withdrawal assay in rhesus monkeys, but only at doses that produce other behavioral and physiological effects.