Injection Of Midazolam Research Articles

Evaluation of the novel antiepileptic drug, AWD 131-138, for benzodiazepine-like discriminative stimulus and reinforcing effects in squirrel monkeys

AWD 131-138 {1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one}, a new low-affinity partial benzodiazepine receptor agonist with potent anticonvulsant and anxiolytic properties in rodent models, was studied in squirrel monkeys trained to discriminate intramuscular (i.m.) injections of midazolam (0.3 mg/kg) from injections of vehicle. Diazepam produced midazolam-like responding at cumulative doses of 1.0 and 3.0 mg/kg i.m. and decreased rates of responding at 3.0 mg/kg (plasma levels of about 400 ng/ml). In contrast, AWD 131-138 did not produce midazolam-like responding or alter response rates at cumulative doses up to 18.0 mg/kg i.m. (plasma levels over 2100 ng/ml). Other monkeys were trained to intravenously (i.v.) self-administer cocaine (56.0 μg/kg/injection). When AWD 131-138 (10–100 μg/kg/injection) was studied by substitution, responding declined to vehicle substitution levels within three sessions. At the dose of 100 μg/kg i.v. AWD 131-138, sufficient drug was self-administered during the first session (about 3.5 mg/kg) to produce plasma levels above 1000 ng/ml, yet responding over the next two sessions dropped to vehicle levels. The failure of AWD 131-138 to produce benzodiazepine-like discriminative effects and the absence of drug self-administration behavior when substituted for cocaine suggest that its abuse liability is low.

The Effect of a Priming Dose of Atracurium on the Onset Time in Rapid Sequence Tracheal Intubation

Background: Depolarizing muscle relaxant, frequently used for rapid sequence endotracheal intubation in clinical field, has serious complication that occur intermittently, such as, hyperkalemia, increased intraoccular pressure and sudden cardiac arm, especially in infants and adolescents. So the priming principle, i.e., the administration of a subparalyzing dose of a nondepolarizing muscle relaxant (priming dose) prior to the intubating dose, was developed for rapid sequence endotracheal intubation with nondepolarizing muscle relaxant. However, the priming dose sometimes causes complications, such as, swallowing difficulty or pulmonary aspiration, and this can cause patient discomfort or fatal complications. In this study we examined proper atracurium priming dose and evaluated possible complications of priming doses. Methods: One hundred patients, scheduled for elective surgery were randomly allocated into five groups according to the priming dose used (group 1; 0, group 2; 0.03, group 3; 0.06, group 4; 0.09, group 5; 0.12 mg/kg). Patients received a midazolam and fentanyl injection, the base line TOF ratio was measured, and an intubating dose was given. We also examined changes in vital sign for 20 minutes after injection and noted the time when the twitch height became zero (onset time). Results: In group 1, the onset time was 107 22.9 sec, and in groups 4 and 5, the onset times were 85.0 15.6 and 69.9 19.3 sec, respectively. But, in group 5, some patients showed tachycardia and swallowing difficulty. Conclusions: The optimal priming dose of atracurium was determined as 0.09 mg/kg, in most cases, however patients sensitivity to the atracurium should be considered.

Mechanisms of action of midazolam on expression of contextual fear in rats

Midazolam may suppress conditioned fear after an aversive event by disrupting the memory trace formed during conditioning, by altering the emotional part of the aversive event, or by the combination of both effects. The purpose of the present study was to determine whether affective-related processes contribute to the amnesic-like effects of midazolam on aversive events. The effects of acute administration of low doses of midazolam (0.37-3 mg kg(-1)) on fear conditioning (association between a neutral context and an aversive stimulus) and on innate anxiety in fearful surroundings were examined in rats. The effect of midazolam on the deleterious consequences of pre-exposure to the context (a non-aversive event) for subsequent fear conditioning was then compared with its effect on fear conditioning. The role of midazolam as an affective context was assessed by performing the testing phase under midazolam. Possible locomotor impairment or long-term effects of midazolam were controlled in additional experiments. Midazolam reduced both contextual fear conditioning and spontaneous fear. The deleterious effect of midazolam on pre-exposure to the context was of the same magnitude as its effect on the acquisition phase of fear conditioning. The effects of midazolam on both pre-exposure to the context and fear conditioning were unchanged when rats received a second injection of midazolam before the retention phase. Low doses of midazolam that do not impair locomotion suppress conditioned fear to the context by acting on memory processes rather than on affective or anxiolytic processes.

Suppression of Spontaneous Scratching in Hairless Rats by Sedatives but Not by Antipruritics

Experimental scratching in animals has hitherto been provoked by substances injected into the skin or central nervous system. We aimed to investigate if spontaneous scratching in the rat can be reduced by sedatives and antipruritics, and to assess if spontaneous scratching is elicited from the skin or the central nervous system. It may also be a complex behaviour related to the rat species, different from clinical itch. Eight male hairless rats were studied for 6 weeks. The animals were recorded on videotape in the middle of the day and at night, and the scratching activity was counted. The following substances were tested sequentially: midazolam, mepyramine, a eutectic mixture of lignocaine and prilocaine (EMLA^®), betamethasone dipropionate and a vehicle. On days 1–3 of each sequence, the test material was applied to a 42-cm² area on the rostral part of the back. Subsequent treatment of the whole body was made on day 4. Midazolam was injected intraperitoneally from day 1 to day 4. After 4 days of treatment, there was a wash-out phase of 3 days until the next sequence. We found a positive correlation between minutes awake and number of scratch episodes. Spontaneous scratching was lower after mepyramine on day 4 (p = 0.046) and after midazolam injections on days 1–3 (p = 0.009) and day 4 (p = 0.003). The local anaesthetic, EMLA, did not significantly influence spontaneous scratching. In conclusion, only the drugs with sedative properties suppressed spontaneous scratching, which is probably a cerebral phenomenon or otherwise explained general behaviour, rather than a reaction to skin stimuli. Thus, for testing of topically applied antipruritics, spontaneous scratching cannot be used as an animal model. Furthermore, evaluation of provocative scratching should eliminate/exclude spontaneous scratching.

Sleep tendency as a measure of recovery after drugs used for ambulatory surgery.

Although tests of psychomotor function indicate that drug effects after ambulatory anesthesia are short-lived, patients often feel washed out for long periods of time. Among the psychomotor tests that measure different motor and cognitive functions, none directly measures sleepiness or alertness. The authors hypothesized that sleepiness, measured by a sleep latency test, would be a more sensitive indicator of drug effect after an anesthetic than psychomotor tests. The second objective was to determine a sedation regimen that produced the least residual effect. On four separate occasions, volunteers (N = 12) received an injection of propofol 2.5 mg/kg; propofol 2.0 mg/kg and fentanyl 2 microg/kg; propofol 2.0 mg/kg and midazolam 2 mg/70 kg; or midazolam 0.07 mg/kg and fentanyl 2 microg/kg. Dependent measures included the multiple sleep latency test (MSLT), Maddox Wing and digit symbol substitution tests, auditory and visual reaction times, and a divided attention task. The multiple sleep latency test demonstrated sleepiness up to 4 h after injection, and in some patients, sleepiness continued up to 8 h afterward. Psychomotor function was impaired only at 2 h after injection of the drug combination. The multiple sleep latency test may be a more sensitive measure of a drug's effect than other tests of psychomotor function. For up to 8 h after an injection of midazolam and fentanyl, patients must consider driving or operating heavy machinery unsafe activities.

Buprenorphine and midazolam act in combination to depress respiration in rats.

High dose buprenorphine is used as substitution treatment in human heroin addiction. Deaths have been reported in addicts using buprenorphine, frequently in association with benzodiazepines. In the current study, we observed the effects of buprenorphine and midazolam alone and in combination on arterial blood gases. Four groups of 10 male Sprague-Dawley rats received a parenteral injection of aqueous solvent, buprenorphine (30 mg/kg, iv), midazolam (160 mg/kg, ip), or buprenorphine (30 mg/kg, iv) plus midazolam (160 mg/kg, ip). Serial blood gases were obtained over 3 hours. There was a mild but significant effect of buprenorphine alone in comparison with the aqueous solvent on PaCO2 at 60 min (6.24 vs. 5.65 kPa, p< 0.01). There was also a mild but significant effect of midazolam alone in comparison with aqueous solvent on arterial pH at 90 min (7.33 vs. 7.41,p< 0.001) and PaCO2 at 60 min (6.52 vs. 5.65 kPa,p< 0.01). The combination of midazolam and buprenorphine produces a rapid, profound, and prolonged respiratory depression, as demonstrated by an increase in PaCO2 at 7.65 +/- 0.12 kPa at 20 min and a decrease in arterial pH at 7.25 +/- 0.02 at 20 min, with appearance of delayed hypoxia with a decrease in PaO2 at 8.74 +/- 0.20 kPa at 120 min. These data show that high doses of midazolam and buprenorphine alone have limited effects on arterial blood gases in rats while midazolam and buprenorphine appear to act in an additive or synergistic fashion to depress ventilation in rats.

Evidence of early placental vascular anastomosis during selective embryo reduction in monozygotic twins

Objective: To describe selective embryo reduction of two triplet pregnancies with a monozygotic twin. Design: Case reports. Setting: Infertility unit of a Department of Obstetrics and Gynecology. Patient(s): Two patients treated with IVF-ET who had triplet pregnancies. Intervention(s): Selective embryo reduction of monozygotic twins. Main Outcome Measure(s): Fetal heart beat. Result(s): During intracardiac injection of potassium chloride plus midazolam in one of the monozygotic twin fetuses, we observed an immediate diminution of the cardiac pulse rate of the second twin. This phenomenon was observed in both patients. Conclusion(s): These observations clearly indicate the presence of vascular anastomosis between the two fetuses of these monozygotic twins. Thus, use of toxic substance to reduce one of the two fetuses of a monozygotic twin pregnancy is contraindicated. In cases of triplets that include a monozygotic twin, it is safest to interrupt the evolution of the twin if selective reduction is desired.

Ventral tegmental lesions reduce overconsumption of normally preferred taste fluid in rats

Previous studies have suggested that the brain regions along the taste pathway and its anatomical interfacing with the brain reward system are concerned with palatability-induced consumption. To clarify whether the ventral tegmental area (VTA) is involved in the behavioral expression induced by taste pleasantness, we examined the effects of lesions to the VTA on the consumption of taste stimuli in rats. (1) Bilateral extensive electrolytic lesions to the VTA selectively reduced the consumption of a normally preferred taste fluid (0.1 M sucrose) compared to that of sham-operated animals during a 24-h two-bottle choice test. The consumption of other fluids, including non-preferred taste fluids (HCl and quinine hydrochloride) was not different between the lesioned and sham animals. (2) The injection of midazolam (3 mg/kg), a benzodiazepine agonist, or morphine (2 mg/kg) significantly increased the consumption of 0.1 M sucrose fluids in the sham animals. The same injections, however, failed to increase intake of the 0.1 M sucrose in rats with 6-hydroxydopamine lesions of the VTA. Neither midazolam nor morphine modified the intake of non-preferred quinine (0.0003 M) solution in both the lesioned and sham animals. These results suggest that dopaminergic mediation in the VTA is required to enhance the consumption of normally preferred fluids exclusively.

Tolerance to the anticonvulsant activity of midazolam and allopregnanolone in a model of picrotoxin seizures

The effects of an intracerebroventricular (i.c.v.) administration of a non-selective full benzodiazepine receptor agonist, midazolam, and a neuroactive steroid, allopregnanolone, on picrotoxin-induced seizures and striatal dopamine metabolism, were studied in mice. It was found that acute i.c.v. injections of midazolam (ED 50=38.25 nmol) and allopregnanolone (ED 50=26.34 nmol) blocked picrotoxin-induced seizures to a similar extent. After repeated administration at the ED 85 doses (midazolam—56.6 nmol, allopregnanolone—94.2 nmol; once or twice daily for 5 days) tolerance developed to the anticonvulsant activity of midazolam (ED 50=94.14 nmol) and allopregnanolone (ED 50=186.70 nmol). Acute i.c.v. injections of midazolam and allopregnanolone (at the ED 50 doses established in the model of picrotoxin seizures: 38.25 and 26.34 nmol, respectively), significantly decreased the concentration of dopamine metabolites: 3-methoxytyramine and 3,4-dihydroxyphenylacetic acid, as well as the dopamine turnover rate (homovanilic acid/dopamine ratio; by about 20%), in the mouse striatum. These findings together with the recently published data on the potentiation by midazolam and allopregnanolone of ethanol-induced sleep [Pharmacol. Biochem. Behav. 67 (2000) 345] indicate a very similar central effect profile of benzodiazepines and neurosteroids. Moreover, similar efficacy of allopregnanolone and midazolam at the GABA A receptors has been found. Overall, the results of the present study, along with the possibility of neurosteroid conversion in the brain into other steroid hormones (testosterone, estradiol, aldosterone), add to the accumulating evidence suggesting a less favorable pharmacological profile for this class of drugs than was previously thought.

Laryngeal mask insertion during target-controlled infusion of propofol

Study Objective: To compare the Laryngeal Mask Airway™ (LMA; The Laryngeal Mask Airway Co., Ltd., Nicosia, Cyprus) insertion conditions produced by 6 and 8 μ g/mL of target plasma concentrations (Cpt) during the induction of anesthesia with target-controlled infusion (TCI) of propofol. Design: Randomized, prospective, single-blind, clinical study. Setting: University hospital. Patients: 44 ASA physical status I and II patients, 16 to 54 years of age, weighing between 45 and 100 kg, undergoing minor surgery in which the use of LMA was indicated. Interventions: Patients were randomly divided into two groups (1 and 2) of 22 to compare the effects of different propofol concentrations. Three minutes after intravenous (IV) injection of midazolam 0.04 mg/kg, group 1 and 2 received TCI of propofol with 6 and 8 μ g/mL of Cpt, respectively. LMA was inserted when the effect-site concentration (EC) reached 2.5 μ g/mL, which was displayed on the infusion pump. Measurements: The LMA insertion conditions (mouth opening, gagging, coughing, head or limb movement, laryngospasm, overall ease of insertion) were assessed, and hemodynamic responses were evaluated until 3 minutes after LMA insertion. Total dose of propofol, EC, and elapsed time since the start of TCI were recorded at five times: at the loss of consciousness and eyelash reflex, at 2.5 μ g/mL of EC, and immediately, 1 minute, and 3 minutes after the insertion of LMA. Main Results: There was no significant difference between the two groups in insertion conditions, despite the significantly larger total dose and shorter elapsed time (2.6 ± 0.08 mg/kg and 109 ± 5.0 s) in Group 2 than those (2.1 ± 0.02 mg/kg and 140 ± 4.1 s) in Group 1 at 2.5 μ g/mL of EC (p < 0.05). Systolic and diastolic blood pressure decreased and heart rate increased significantly throughout the study period in both groups (p < 0.05). But there was a significant decrease in arterial pressure in Group 2 compared with Group 1 1 and 3 minutes after the insertion (p < 0.05). Conclusions: Induction with 8 μ g/mL of Cpt, compared with 6 μ g/mL, allowed earlier LMA insertion but, could not improve the conditions for LMA insertion and required more careful attention to the decrease in blood pressure after LMA insertion.

Usefulness of midazolam premedication for volatile induction of anesthesia in adults.

Induction of anesthesia can be achieved rapidly using the vital capacity (“single breath”) technique with 8% sevoflurane, which typically produces loss of consciousness in 45‐55 s [1‐3]. This technique using sevoflurane is associated with minimal complications compared with those using halothane [4,5] or isoflurane [6]. Although sevoflurane has little pungency, patients sometimes complain about the discomfort of the induction. We therefore investigated the effect of premedication with midazolam for smoother induction and for the patient’s comfort. One hundred adult patients with ASA physical status I or II who required general anesthesia for minor surgery were enrolled in this study. Patients with a history of, or evidence from laboratory or physical examination indicating, hepatic, renal, or significant respiratory or cardiovascular disease were excluded from the study. The patients were randomly divided into two groups (by the coin technique): control (n 5 48) and midazolam (n 5 52) groups. Intramuscular injection of midazolam (2‐ 3 mg) was given to the midazolam group 1 h before anesthesia, whereas no premedication was given to the control group. While the patients were breathing room air before the induction of anesthesia, the anesthetic circuit was circulated with 10 l·min 21 oxygen and 5% sevoflurane for 1 min. The patients were instructed to breathe out to residual volume, and then the anesthetic mask was fitted tightly. They were then told to take

Estrus variation in anticonflict effects of midazolam microinjected into septal nuclei in female Wistar rats

Effects of midazolam intraperitoneally (3.0 mg/kg) administered, or locally applied into lateral septal nuclei (10 μg/μl), or into the medial septum (10 μg/μl) were assessed in Wistar rats during late proestrus or metestrus–diestrus in a conflict-operant task. A reduction in conflict behavior was found in control rats during late proestrus ( P<.05), when compared to metestrus–diestrus. Systemic injections of midazolam ( P<.05) or midazolam infusions into lateral septal nuclei ( P<.05) also reduced conflict behavior only during late proestrus, whereas midazolam infusions into the medial septum produced neither of these anticonflict effects in any estrous phase. In conclusion, an endocrine-related variation in anticonflict effects of midazolam microinjected into lateral septal nuclei was displayed by female rats.

Oral transmucosal midazolam premedication for preschool children

To evaluate the acceptance and effectiveness of 0.2 mg x kg(-1) of oral transmucosal midazolam as a premedicant in infants and preschool children. In a randomized, prospective double-blind placebo controlled study, 44 healthy children, between the ages of eight months to six years, presenting for elective surgery were divided in two groups. The medicated group received 0.2 mg x kg(-1) of injectable midazolam mixed with an equal volume of strawberry syrup and the placebo group received plain syrup 0.08 ml x kg(-1). Medications were placed on the anterosuperior aspect of the child's tongue in 3-5 aliquots of 0.2-0.4 ml. A blinded observer assessed the acceptance of the medication by willingness to open the mouth for the next aliquot and the efficacy of the medication was assessed by ease of separation from the parent. Ninety-six percent of the children in the placebo group and 95% in the midazolam group willingly accepted the medication. Separation of children from parents was successful in 95% of the medicated children compared with 59% in the placebo group (P = 0.006). Oral midazolam in thick strawberry syrup, administered in small aliquots via the oral transmucosal route was well accepted and proved to be an effective premedicant in infants and preschool children.

The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-induced seizures, and a hypnotic effect of ethanol

The effects of intraperitoneally (IP) or intracerebroventricularly (ICV) administered neurosteroids [allopregnanolone (AP); 5β-tetrahydrodeoxycorticosterone (5β-THDOC); dehydroepiandrosterone sulfate (DHEAS); pregnenolone sulfate (PS)] and their precursors [progesterone (PROG), pregnanedione (PREG)] on N-methyl- d-aspartic acid (NMDA)-, picrotoxin (PTX)- and bicuculline (BIC)-induced seizures and ethanol-induced sleep were studied in mice. It was found that IP injections of (+)MK-801 most potently antagonized NMDA-, PTX- and BIC-induced seizures, as compared to diazepam (DZP), PROG and PREG. Both precursors of neurosteroids appeared only marginally active in the applied models of convulsions. ICV injections of AP selectively blocked PTX- and BIC-induced seizures, whereas 5β-THDOC and (+)MK-801 also antagonized NMDA-induced convulsions. ICV administered DHEAS induced seizures in a dose-dependent way. ICV injections of AP and midazolam shortened the latency and prolonged the duration of sleep induced by IP injections of ethanol (5.0 g/kg). On the contrary, DHEAS and PS significantly reduced the hypnotic-like effect of ethanol. The obtained results suggest that neurosteroids may modulate in an agonistic (AP, 5β-THDOC), or antagonistic way (PS, DHEAS), the GABA A receptor complex functions. Some of them (5β-THDOC) also interact with NMDA receptors. AP appeared to be the most selectively acting compound, with its profile of action fully comparable to that of midazolam. AP also enhanced the hypnotic effect of ethanol, pointing out to the propensity to interact with centrally depressant agents. These findings, together with the possibility of conversion of some neurosteroids in the brain to other steroid hormones (testosterone, estradiol and aldosterone), indicate the limitations of their use for the treatment of neurological and psychiatric disorders.

Acute Phase Histopathological Study of Spinally Administered Midazolam in Cats

Acute Phase Histopathological Study of Spinally Administered Midazolam in Cats

THE INFLUENCE OF LIDOCAINE AND VERAPAMIL ON HAEMODYNAMIC PARAMETERS AFTER INTRAVENOUS ADMINISTRATION OF MIDAZOLAM IN RABBITS

Cardiac arrhythmia can be a serious complication during general anaesthesia of patients suffering from cardiac arrhythmias and using antiarrhythmic drugs. The aim of the present experiments was to establish the way in which lidocaine and verapamil influence haemodynamic parameters of rabbits after midazolam anaesthesia. The experiments were performed on rabbits. Heart rate was counted according to ECG. Blood pressure was measured directly in the carotid artery. Cardiac output, stroke volume, and total peripheral resistance were estimated using the method of human125J albumin dilution. Midazolam caused a gradual fall of arterial blood pressure till 30 min of the experiment. The decrease of blood pressure in the first 45 min of the experiment might be a result of decreasing peripheral resistance, and after 60 min should be rather attributed to a decrease of cardiac output and stroke volume. Lidocaine did not change the influence of midazolam on the blood pressure and heart rate. The consequence was a decrease of blood pressure after midazolam and lidocaine administration. Combined administration of midazolam and lidocaine decreased the influence of both midazolam and lidocaine on the total peripheral resistance. An injection of midazolam with verapamil resulted in a significant decrease of blood pressure. Combined administration of midazolam and verapamil caused a significant decrease of heart rate as compared with the initial value and administration of midazolam alone. 1999 Academic Press@p$hr

The Clinical Outcome of Abdominoplasty Performed under Conscious Sedation: Increased Use of Fentanyl Correlated with Longer Stay in Outpatient Unit

The objective of this study was to present data supporting the effectiveness of performing mini and full abdominoplasties under conscious sedation with local anesthesia. The authors performed 20 such operations between 1994 and 1996, using a combination of midazolam (Versed) and fentanyl instead of general anesthesia (without an anesthesiologist or nurse anesthetist present). At 5- to 10-minute intervals, the surgeon would order the injection of 1 cc (1 mg/ml) of midazolam and 1 cc (50 microg/ml) of fentanyl. The amount and the interval varied based on the patient's level of sedation. Blood pressure, oxygen saturation, and the patient's response to verbal and physical stimuli were used to assess the sedation level. Average operating time was 147.5 minutes, and mean length of stay in the outpatient recovery room was 235.5 minutes. The average amounts of midazolam and fentanyl used were 9.4 mg (6 to 12.5 mg) and 532 microg (300 to 800 microg), respectively. The average age of patients in this group was 41.7 years (28 to 63 years). Nineteen patients were discharged the same day. There were no surgical complications and no complication related to the sedation (such as respiratory or cardiac compromise). The average follow-up of these patients was 1.2 years (range, 3 to 21 months). Correlation coefficient rates and regression rates were calculated. The longer the procedure, the more midazolam was used intraoperatively (r = 0.5, p = 0.03). However, there was no correlation between the length of the procedure and the amount of fentanyl used. Rather, there was a positive correlation demonstrating that patients who received more fentanyl stayed longer in the outpatient recovery area after surgery (r = 0.6, p < 0.01). The age of the patients and the amount of midazolam did not correlate with how fast they went home from the outpatient area. In conclusion, full and mini abdominoplasties can be performed safely using conscious sedation without compromising patient care or surgical outcome. Second, the survey revealed that patient satisfaction with these procedures performed under conscious sedation was very high. Third, the increased use of fentanyl, not midazolam, resulted in a longer stay in the outpatient unit after surgery. Nausea is a known side effect of narcotic analgesics, and it correlated with a higher dose of fentanyl administration in the patients. The authors are now routinely administering a dose of either droperidol or odansetron (Zofran) preoperatively (both are antiemetics). Previously, the ratio of midazolam and fentanyl injection was 1:1 every 5 to 10 minutes, but now it is 2: 1 to 4: 1 every 5 to 10 minutes (a smaller dose of fentanyl is administered). The conscious sedation technique should be an option for patients and plastic surgeons in academic and community hospital settings if they desire.

The Neurotoxicity of Drugs Given Intrathecally (Spinal)

The Neurotoxicity of Drugs Given Intrathecally (Spinal)

Midazolam-induced hyperalgesia in rats: modulation via GABA A receptors at supraspinal level

The effect of benzodiazepines on the nociceptive threshold was studied in rats using the tail-flick and the formalin tests. Systemic injection of midazolam (10 mg/kg, i.p.) induced a significant decrease of the tail-flick latency and produced a long-lasting nociceptive effect in the formalin test, thus characterising a hyperalgesic state. The hyperalgesia induced by midazolam in the tail-flick test was blocked by flumazenil, a specific antagonist for benzodiazepine sites associated with GABA A receptors. Picrotoxin, a Cl − channel blocker, inhibited midazolam-induced hyperalgesia in both tests. Midazolam caused hyperalgesia when administered intracerebroventricularly (i.c.v.; 25 μg) but not intrathecally (i.t.; 75 μg). I.c.v. but not i.t. (5 μg) injection of flumazenil suppressed the hyperalgesia induced by midazolam (10 mg/kg, i.p.). Combination of non-hyperalgesic doses of diazepam (10 mg/kg, i.p.) or ethanol (0.48 g/kg, oral) with midazolam (5 mg/kg, i.p.) also induced hyperalgesia. Our results demonstrate that midazolam and diazepam alone or in combination with ethanol can produce hyperalgesia by interacting with GABA A receptors at the supraspinal level in rats. The risk of hyperalgesia should be taken in account when these drugs are used in combination in humans.

Anxiolytic effect of intra-amygdala injection of midazolam and 8-hydroxy-2-(di- n-propylamino)tetralin in the elevated T-maze

The effects of intra-amygdala injection of midazolam (20 nmol) and 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT; 8 and 16 nmol) were investigated in rats submitted to the elevated T-maze, a new animal model of anxiety. This test allows the measurement, in the same rat, of conditioned and unconditioned fear/anxiety responses. Both drugs impaired inhibitory avoidance of the open arms of the T-maze (task representing conditioned fear), indicating an anxiolytic effect, but did not change escape performance from one of the open arms (representing unconditioned fear). The results further implicate γ-aminobutyric acid (GABA)/benzodiazepine and serotonergic systems within the basolateral/lateral amygdala in the modulation of conditioned anxiety responses.