Hajhashemi V, Dehdashti Kh
Department of Pharmacology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.
Res Pharm Sci. 2014 Sep-Oct;9(5):315-21.
Glutamate has a key role in pain perception and also development of tolerance and dependence to morphine. It has been reported that clavulanic acid affects glutamatergic transmission via activation of glutamate transporter. Therefore the present study was aimed to evaluate the possible antinociceptive effect of clavulanic acid and its preventive activity against development of morphine tolerance and dependence in animal models. Male Swiss mice (25-30 g) were used in this study. Acetic acid-induced writhing, formalin test and hot plate method were used to assess the antinociceptive effect of clavulanic acid. Morphine (30 mg/kg, s.c.) was administered to the mice two times a day (8 AM and 4 PM) for 3 days in order to produce tolerance. To develop morphine dependence, morphine sulfate (50, 50 and 75 mg/kg) was injected at 8 and 12 AM and 16 PM respectively and for 3 consecutive days. Naloxone (5 mg/kg, i.p) was used to induce morphine withdrawal syndrome and the number of jumps and presence of ptosis, piloerection, tremor, sniffing and diarrhea were recorded and compared with control group. Clavulanic acid at doses of 10, 20 and 40 mg/kg inhibited abdominal constriction and licking behavior of acetic acid and formalin-induced pain respectively. Clavulanic acid was not able to show any antinociception in hot plate model and could not prevent development of tolerance and dependence to morphine. Clavulanic acid has considerable antinociceptive activity and further studies are needed to clarify its exact mechanism.
谷氨酸在疼痛感知以及对吗啡的耐受性和依赖性形成过程中发挥着关键作用。据报道，克拉维酸通过激活谷氨酸转运体影响谷氨酸能传递。因此，本研究旨在评估克拉维酸在动物模型中可能的抗伤害感受作用及其对吗啡耐受性和依赖性形成的预防活性。本研究使用雄性瑞士小鼠（25 - 30克）。采用乙酸诱导扭体试验、福尔马林试验和热板法评估克拉维酸的抗伤害感受作用。为产生耐受性，给小鼠每天皮下注射两次吗啡（30毫克/千克），共3天（上午8点和下午4点）。为形成吗啡依赖性，分别在上午8点、12点和下午4点给小鼠注射硫酸吗啡（50、50和75毫克/千克），连续3天。腹腔注射纳洛酮（5毫克/千克）诱导吗啡戒断综合征，并记录跳跃次数以及睑下垂、竖毛、震颤、嗅探和腹泻的情况，并与对照组进行比较。剂量为10、20和40毫克/千克的克拉维酸分别抑制了乙酸诱导的腹部收缩和福尔马林诱导疼痛的舔舐行为。克拉维酸在热板模型中未显示出任何抗伤害感受作用，也无法预防对吗啡耐受性和依赖性的形成。克拉维酸具有相当的抗伤害感受活性，需要进一步研究以阐明其确切机制。
