Galeotti Nicoletta, Bartolini Alessandro, Ghelardini Carla
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
Neuropharmacology. 2004 Nov;47(6):935-44. doi: 10.1016/j.neuropharm.2004.07.001.
The role of intracellular calcium in acute thermal nociception was investigated in the mouse hot-plate test. Intracerebroventricular (i.c.v.) administration of TMB-8, a blocker of Ca++ release from intracellular stores, produced hypernociception. By contrast, i.c.v. pretreatment with thapsigargin, a depletor of Ca++ intracellular stores, produced an increase of the mouse pain threshold. Furthermore, non-analgesic doses of thapsigargin prevented the hypernociception produced by TMB-8. In mice undergoing treatment with heparin, an InsP3-receptor antagonist, or ryanodine, a ryanodine receptor (RyR) antagonist, a dose-dependent reduction of the pain threshold was observed. Pretreatment with D-myo inositol, compound which produces InsP3, and 4-chloro-m-cresol, a RyR agonist, induced an antinociceptive effect. The heparin hypernociception was prevented by D-myo inositol, but not by L-myo inositol, used as negative control. In the same experimental conditions, the antinociception induced by D-myo inositol was prevented by a non-hyperalgesic dose of heparin. Similarly, the reduction of pain threshold produced by ryanodine was reversed by non-analgesic doses of 4-chloro-m-cresol, whereas the antinocicpetion induced by 4-chloro-m-cresol was prevented by non-hyperalgesic doses of ryanodine. The pharmacological treatments employed did not produce any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate that a variation of intracellular calcium contents at a supraspinal level is involved in the modulation of acute thermal nociception. In particular, the stimulation of both InsP3- and Ry-receptors appears to play an important role in the induction of antinociception in mice, whereas a blockade of these receptors is involved in an hypernociceptive response to acute thermal pain.
在小鼠热板试验中研究了细胞内钙在急性热痛觉感受中的作用。脑室内（i.c.v.）注射TMB - 8（一种细胞内钙库Ca++释放的阻滞剂）会产生痛觉过敏。相比之下，脑室内预先注射毒胡萝卜素（一种细胞内钙库排空剂）会使小鼠痛阈升高。此外，非镇痛剂量的毒胡萝卜素可预防TMB - 8产生的痛觉过敏。在用肝素（一种肌醇三磷酸（InsP3）受体拮抗剂）或ryanodine（一种兰尼碱受体（RyR）拮抗剂）治疗的小鼠中，观察到痛阈呈剂量依赖性降低。用D - 肌醇（产生InsP3的化合物）和4 - 氯间甲酚（一种RyR激动剂）进行预处理可诱导镇痛作用。肝素引起的痛觉过敏可被D - 肌醇预防，但用作阴性对照的L - 肌醇则不能。在相同实验条件下，D - 肌醇诱导的镇痛作用可被非痛觉过敏剂量的肝素阻断。同样，ryanodine引起的痛阈降低可被非镇痛剂量的4 - 氯间甲酚逆转，而4 - 氯间甲酚诱导的镇痛作用可被非痛觉过敏剂量的ryanodine阻断。如转棒试验和洞板试验所示，所采用的药物治疗未对小鼠产生任何行为损害。这些结果表明，脊髓上水平的细胞内钙含量变化参与了急性热痛觉感受的调节。特别是，InsP3受体和Ry受体的刺激在小鼠镇痛诱导中似乎起重要作用，而这些受体的阻断则参与了对急性热痛的痛觉过敏反应。
