Gray A M, Nevinson M J, Sewell R D
Division of Pharmacology, The Welsh School of Pharmacy, University of Wales, Cathays Park, Cardiff, UK.
Eur J Pharmacol. 1999 Jan 22;365(2-3):149-57. doi: 10.1016/s0014-2999(98)00837-1.
Nefopam is a clinically effective analgesic agent used to control mild to moderate pain, whose mechanism of action is unknown. We have investigated the antinociceptive activity of nefopam in the mouse abdominal constriction assay and tail immersion test (48 degrees C). Nefopam was found to possess a high degree of potency against acetic acid-induced visceral nociception (ED50 2.5 mg kg(-1)). In the presence of the opioid receptor antagonists, naloxone or naltrindole, the resulting nefopam dose-response relationships were shifted to the right. Naloxone or naltrindole had no effect upon aspirin (ED50 32.1 mg kg(-1)) or clonidine (ED50 0.061 mg kg(-1)) induced antinociception. Acetorphan (10 mg kg(-1); s.c.), an inhibitor of neutral endopeptidase (EC 3.4.24.11) was able to potentiate nefopam's antinociceptive activity (ED50 1.5 mg kg(-1)). The alpha2-adrenoceptor antagonist, 2-[2-(2-methoxy-1,4-benzodioxanyl)]imidazoline hydrochloride (RX821002; 1 mg kg(-1); s.c.), shifted the dose-response curves for clonidine (ED50 7.1 mg kg(-1)) and nefopam (ED50 5.3 mg kg(-1)) to the right in this assay. Additionally, centrally administered RX821002 (1 microg/5 microl/animal; i.c.v.) reduced both clonidine (ED50 7.2 mg kg(-1)) and nefopam's ED50 15.5 mg kg(-1)) efficacy in the abdominal constriction assay. Nefopam (3 and 7.5 mg kg(-1); s.c.) produced significant antinociceptive effect in the thermal assay. Aspirin and RX821002 were devoid of any significant activity in the tail immersion test. Nefopam was shown to possess RX821002-reversible antinociceptive activity in both the tail immersion test and the abdominal constriction assay. These data suggest the involvement of an opioidergic and noradrenergic component to nefopam's antinociceptive activity in the mouse abdominal constriction assay and tail immersion test. However, the present results are unable to determine if the opioidergic component of nefopam antinociception is through a direct and/or indirect activation of opioid receptors.
奈福泮是一种用于控制轻至中度疼痛的临床有效镇痛药，其作用机制尚不清楚。我们在小鼠腹部收缩试验和尾部浸没法（48℃）中研究了奈福泮的抗伤害感受活性。发现奈福泮对乙酸诱导的内脏伤害感受具有高度效力（半数有效量为2.5mg/kg）。在存在阿片受体拮抗剂纳洛酮或纳曲吲哚的情况下，所得到的奈福泮剂量-反应关系向右移动。纳洛酮或纳曲吲哚对阿司匹林（半数有效量为32.1mg/kg）或可乐定（半数有效量为0.061mg/kg）诱导的抗伤害感受无影响。中性内肽酶（EC 3.4.24.11）抑制剂醋托芬（10mg/kg；皮下注射）能够增强奈福泮的抗伤害感受活性（半数有效量为1.5mg/kg）。α2-肾上腺素能受体拮抗剂2-[2-(2-甲氧基-1,4-苯并二氧杂环己烯基)]咪唑啉盐酸盐（RX821002；1mg/kg；皮下注射）使可乐定（半数有效量为7.1mg/kg）和奈福泮（半数有效量为5.3mg/kg）在该试验中的剂量-反应曲线向右移动。此外，在腹部收缩试验中，脑室内给予RX821002（1μg/5μl/动物）降低了可乐定（半数有效量为7.2mg/kg）和奈福泮（半数有效量为15.5mg/kg）的效力。奈福泮（3mg/kg和7.5mg/kg；皮下注射）在热试验中产生了显著的抗伤害感受作用。阿司匹林和RX821002在尾部浸没法中无任何显著活性。在尾部浸没法和腹部收缩试验中，奈福泮均表现出对RX821002可逆的抗伤害感受活性。这些数据表明，在小鼠腹部收缩试验和尾部浸没法中，阿片样物质能和去甲肾上腺素能成分参与了奈福泮的抗伤害感受活性。然而，目前的结果无法确定奈福泮抗伤害感受的阿片样物质能成分是否通过直接和/或间接激活阿片受体发挥作用。
