Comparison of Short-And Long-Acting Benzodiazepine-Receptor Agonists
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J Pharmacol Sci 107, 277 – 284 (2008)3 Journal of Pharmacological Sciences ©2008 The Japanese Pharmacological Society Full Paper Comparison of Short- and Long-Acting Benzodiazepine-Receptor Agonists With Different Receptor Selectivity on Motor Coordination and Muscle Relaxation Following Thiopental-Induced Anesthesia in Mice Mamoru Tanaka1, Katsuya Suemaru1,2,*, Shinichi Watanabe1, Ranji Cui2, Bingjin Li2, and Hiroaki Araki1,2 1Division of Pharmacy, Ehime University Hospital, Shitsukawa, Toon, Ehime 791-0295, Japan 2Department of Clinical Pharmacology and Pharmacy, Neuroscience, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan Received November 7, 2007; Accepted May 15, 2008 Abstract. In this study, we compared the effects of Type I benzodiazepine receptor–selective agonists (zolpidem, quazepam) and Type I/II non-selective agonists (zopiclone, triazolam, nitrazepam) with either an ultra-short action (zolpidem, zopiclone, triazolam) or long action (quazepam, nitrazepam) on motor coordination (rota-rod test) and muscle relaxation (traction test) following the recovery from thiopental-induced anesthesia (20 mg/kg) in ddY mice. Zolpidem (3 mg/kg), zopiclone (6 mg/kg), and triazolam (0.3 mg/kg) similarly caused an approximately 2-fold prolongation of the thiopental-induced anesthesia. Nitrazepam (1 mg/kg) and quazepam (3 mg/kg) showed a 6- or 10-fold prolongation of the anesthesia, respectively. Zolpidem and zopiclone had no effect on the rota-rod and traction test. Moreover, zolpidem did not affect motor coordination and caused no muscle relaxation following the recovery from the thiopental-induced anesthesia. However, zopiclone significantly impaired the motor coordination at the beginning of the recovery. Triazolam significantly impaired the motor coordination and muscle relaxant activity by itself, and these impairments were markedly exacerbated after the recovery from anesthesia. Nitrazepam and quazepam significantly impaired motor coordination, and the impairments were exacerbated after the recovery. These results suggest that the profile of recovery of motor coordination and muscle flaccidity after co-administration of benzodiazepine-receptor agonists and thiopental is related to the half-life and selectivity for the benzodiazepine-receptor subtypes. Keywords: hypnotics, thiopental, loss of righting reflex, motor coordination, muscle relaxant Introduction studies have revealed that the impaired coordination and balance induced by hypnotics or benzodiazepines are A meta-analysis suggested that short-acting hypnotics associated with falls (1, 5). Patient falls are an important may be effective for the short-term treatment of situa- issue in risk management for hospitalized patients and tional insomnia (1). However, despite their therapeutic elderly people in nursing homes (6). Such accidents may effectiveness, many hypnotics, such as the benzodiaz- lead to negative outcomes, such as injuries, prolonged epine derivative triazolam, cyclopyrrolone derivative hospitalization, reduction in patients’ activities of daily zopiclone, and imidazopyridine derivative zolpidem, living, and increased medical expenses. Previous studies have some side effects, including impaired coordination of benzodiazepine regimens, which may be associated and balance, cognitive impairment, tolerance, and with a risk of adverse events, have produced conflicting dependence (2 – 4). In addition, a number of clinical results. Early investigations of benzodiazepines with different elimination half-lives have suggested that long- *Corresponding author. [email protected] acting benzodiazepines are more likely to cause adverse Published online in J-STAGE on July 5, 2008 (in advance) events than short-acting agents (7, 8). However, other doi: 10.1254/jphs.FP0071991 studies have found significantly greater risks of adverse 277 278 M Tanaka et al effects with the use of short-acting agents (1, 9). These 20 – 30 g were used in all of the experiments. All of the results indicate that falls are a complex phenomenon animals were housed in groups of five per plastic cage with multifactorial causes such as age, health conditions, (18 × 44 × 27 cm) in a room maintained at 22 ± 2°C and concomitant medications in the clinical settings. under a 12/12-h light/dark cycle with lights on at Therefore, studies using experimental animals are 7:00 AM. The experimental protocol was conducted important to clarify the pharmacological profile of according to the Guidelines of the Ethics Review benzodiazepine-receptor agonists. Committee for Animal Experimentation of Ehime Several benzodiazepine-receptor agonists with recep- University Medical School. tor subtypes or different elimination half-lives have been developed. Molecular biological studies have demon- Drugs strated that the GABAA receptor is a pentamer consisting The following drugs were used: zolpidem (Astellas of subunits from at least five different families, of which Pharmaceutical Co., Ltd., Osaka), zopiclone (Sanofi- the α-, β-, and γ-subunits are generally considered Aventis Co., Ltd., Tokyo), nitrazepam and triazolam necessary for modulation by benzodiazepine-receptor (Sigma-Aldrich, Inc., St. Louis, MO, USA), quazepam agonists (10, 11). Zolpidem and quazepam bind (Mitsubishi Pharma Co., Ltd., Tokyo), and thiopental selectivity to Type-I (ω1) benzodiazepine receptors sodium (Ravonal®; Tanabe Seiyaku Co., Osaka). (GABAA-receptor subtypes α1 containing subunits) Zopiclone, triazolam, nitrazepam, and quazepam were (12 – 14). Type-II (ω2) benzodiazepine receptors contain dissolved in 0.5% polypropylene glycol (PPG), and α1-, α2-, α3-, and α5-subunits; and zopiclone, triazolam, zolpidem and thiopental sodium were dissolved in and nitrazepam are non-selective for Types I and II physiological saline (0.9% sodium chloride). The benzodiazepine receptors (13, 15). The benzodiazepine- thiopental sodium was injected intravenously, and the receptor agonists were also classified based on their hypnotics were injected intraperitoneally at a volume of pharmacokinetic characteristics: ultra-short–acting (half- 0.1 ml per 10 g body weight. life <6 h) such as zolpidem, zopiclone, and triazolam; short-acting (half-life 6 – 12 h); intermediate-acting Loss of righting reflex (half-life 12 – 24 h); and long-acting (half-life >24 h) The mice were injected with thiopental (20 mg/kg, such as nitrazepam and quazepam (16, 17). i.v.) in order to induce hypnosis, which was defined as a Previous studies have demonstrated the pharmaco- loss of the righting reflex. In a preliminary study, we logical actions of hypnotics at the time of sleep induction investigated which doses of ultra-short acting hypnotics and during sleep (18 – 22). For the evaluation of the side with thiopental were required to induce a similar loss of effects of benzodiazepine-receptor agonists, rota-rod the righting reflex. Zolpidem (3 and 10 mg/kg, i.p.), and traction tests have been used as screening methods zopiclone (3 and 6 mg/kg, i.p.), and triazolam (3 mg/kg, for an impairment of motor coordination or muscle i.p.) were administered 10 min before the injection of relaxant effects in rodents (21). However, little is known thiopental, and the long-acting hypnotics, nitrazepam about their pharmacological actions just after awaken- (0.6 and 1 mg/kg, i.p.) and quazepam (3 mg/kg, i.p.), ing. On the other hand, thiopental is a rapidly acting were administered 20 min before the injection of barbiturate and a single intravenous injection of thio- thiopental. The control mice were administered pental produces only a brief period of hypnosis and thiopental and vehicle containing the hypnotic solution anesthesia (22). Therefore, in this study, we applied the (saline or 0.5% PPG). Loss of the righting reflex was thiopental-induced hypnosis to the evaluation of side induced immediately after the injection of thiopental. effects of benzodiazepine receptor agonists after awaken- Thereafter, the mice were placed in a V-shaped support ing. in the supine position until recovery under a heat lamp to In this study, we examined the effects of zolpidem, maintain normal temperature, and the duration of the zopiclone, triazolam, quazepam, and nitrazepam on the loss of the righting reflex was measured. In the rota-rod impairment of motor coordination using the rota-rod and traction tests, the mice were administered zolpidem test and muscle relaxant activity using the traction test (3 mg/kg, i.p.), zopiclone (6 mg/kg, i.p.), triazolam (0.3 during the recovery phase from thiopental-induced mg/kg, i.p.) nitrazepam (1 mg/kg, i.p.), or quazepam anesthesia in mice. (3 mg/kg, i.p.); and these tests were performed at 15, 30, and 60 min after recovery from the loss of the righting Materials and Methods reflex. Animals Traction test Male ddY mice (SLC Co., Ltd., Shizuoka) weighing The grip strength of each mouse was measured with a Hypnotics and Side Effects 279 traction apparatus (23). The forepaws of the mouse were Table 1. The duration of the loss of the righting reflex induced by placed on the attached bar (2-mm diameter, 30-cm-long, the combination of thiopental and hypnotics 30-cm above the bench level) and the latency until Duration of the loss Treatment Dose n falling occurred was monitored for 60 s. of righting reflex (s) Saline 1 ml/kg 7 113.1 ± 24.5 Rota-rod test ± The rota-rod test (24) has been used to assess motor Zolpidem 3 mg/kg 7 205.3 62.6 ± a coordination and balance alterations in rodents. In this 10 mg/kg 7 1109.1 122.1 study, we used a rotating rod (3-cm diameter) apparatus 0.5% PPG 1 ml/kg 7 117.3 ± 15.0 (UGO BASILE, Comerio, Italy). The rota-rod test was Zopiclone 3 mg/kg 7 146.3 ± 41.6 performed under accelerating conditions: each mouse 6mg/kg 9 227.2 ± 67.4 was placed on the rod rotating from 3 to 30 rpm over 3 min. The time the animal was able to maintain its Triazolam 0.3 mg/kg 7 234.8 ± 39.5 balance walking on top of the rod was measured. The Nitrazepam 0.6 mg/kg 6 225.5 ± 35.5 mice were given two trials with a maximum time of 1mg/kg 7 655.6 ± 172.4b 180 s.