Ghelardini C, Galeotti N, Figini M, Imperato A, Nicolodi M, Sicuteri F, Gessa G L, Bartolini A
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
J Pharmacol Exp Ther. 1996 Nov;279(2):884-90.
The antinociceptive effect of the antimigraine drug sumatriptan was assessed in mice and rats (hot-plate, abdominal constriction and paw-pressure tests) and in guinea pigs (paw-pressure test). The ACh extracellular concentration also was detected in the hippocampus of freely moving rats by microdialysis experiments. Antinociception was induced by sumatriptan administered both parenterally (5-10 mg.kg-1 i.v.; 10-30 mg.kg-1 i.p.) and i.c.v. (50-100 micrograms per mouse). Sumatriptan antinociception was potentiated by physostigmine (0.05 mg.kg-1 i.p.) and was prevented by the muscarinic antagonist atropine (5 mg.kg-1 i.p.), the ACh depletor HC-3 (1 micrograms per mouse i.c.v.) and the 5-hydroxytryptamine1A antagonist 1-(2-methoxyphenyl)-4-[4-(2 phthalimido)butyl] piperazine (0.5 mg.kg-1 i.p.). Naloxone, 3-aminopropyl-diethoxy-methyl-phosphinc acid, 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino) ethyl ester and reserpine, administered in doses suitable for blocking analgesi induced by morphine, baclofen, 5-hydroxytryptamine4 agonist and clomipramine, respectively, did not modify sumatriptan antinociception. Sumatriptan, administered in the range of antinociceptive doses, was able to increase the level of ACh present in extracellular hippocampal space. On the basis of these findings we can deduce that sumatriptan was able to induce antinociception by increasing cholinergic activation in the CNS. Such activation, as indicated by the antagonism exerted by 1-(2-methoxyl-phenyl)-4-[4-(2 pethalimido)butyl]piperazine, may depend on stimulation of 5-hydroxytryptamine1A autoreceptors. It remains to be clarified whether the antimigraine activity of sumatriptan in humans is totally dependent on cranial vessel vasoconstriction of whether its central cholinergic antinociception also plays a role.
在小鼠和大鼠中（热板法、腹部收缩法和爪压试验）以及豚鼠中（爪压试验）评估了抗偏头痛药物舒马曲坦的镇痛作用。通过微透析实验在自由活动大鼠的海马体中检测乙酰胆碱细胞外浓度。舒马曲坦通过胃肠外给药（静脉注射5 - 10mg·kg⁻¹；腹腔注射10 - 30mg·kg⁻¹）和脑室内给药（每只小鼠50 - 100微克）均可诱导镇痛作用。毒扁豆碱（腹腔注射0.05mg·kg⁻¹）可增强舒马曲坦的镇痛作用，而毒蕈碱拮抗剂阿托品（腹腔注射5mg·kg⁻¹）、乙酰胆碱耗竭剂HC - 3（每只小鼠脑室内注射1微克）和5 - 羟色胺1A拮抗剂1 - (2 - 甲氧基苯基)-4 - [4 - (2 - 邻苯二甲酰亚胺基)丁基]哌嗪（腹腔注射0.5mg·kg⁻¹）可抑制该作用。纳洛酮、3 - 氨丙基 - 二乙氧基 - 甲基 - 膦酸、2 - 甲氧基 - 4 - 氨基 - 5 - 氯苯甲酸2 - (二乙氨基)乙酯和利血平，分别以适合阻断吗啡、巴氯芬、5 - 羟色胺4激动剂和氯米帕明诱导的镇痛作用的剂量给药，并未改变舒马曲坦的镇痛作用。在镇痛剂量范围内给药的舒马曲坦能够增加海马体细胞外空间中乙酰胆碱的水平。基于这些发现我们可以推断，舒马曲坦能够通过增强中枢神经系统中的胆碱能激活来诱导镇痛作用。如1 - (2 - 甲氧基苯基)-4 - [4 - (2 - 邻苯二甲酰亚胺基)丁基]哌嗪所发挥的拮抗作用所示，这种激活可能取决于对5 - 羟色胺1A自身受体的刺激。舒马曲坦在人类中的抗偏头痛活性是否完全依赖于颅血管收缩，或者其中枢胆碱能镇痛作用是否也起作用，仍有待阐明。
