Rattan A K, Tejwani G A
Department of Pharmacology and Anesthesiology, Ohio State University College of Medicine, Columbus.
Pharmacology. 1994 Jan;48(1):30-40. doi: 10.1159/000139159.
Midazolam, a benzodiazepine receptor agonist, when injected intrathecally either enhances or decreases antinociception produced by intrathecal administration of morphine in rats. Furthermore, midazolam inhibits binding of several opioid ligands to spinal opioid receptors in vitro [Rattan et al, Anesth Analg 1991;73:124-131]. This study was designed to investigate the effect of midazolam on binding of mu-, delta- and kappa-ligands to rat spinal opioid receptors in the presence of sodium ions which differentially modulate binding of opioid agonists and antagonists. Sodium ions (50-1,000 mmol/l) selectively increased the specific binding of [3H]naloxone but decreased binding of opioid agonists such as [3H]DAGO (Tyr-D-Ala-Gly-Methyl-Phe-Gly-ol-enkephalin) to mu-receptors, [3H]DSTLE (Tyr-D-Ser-Gly-Phe-Leu-Thr-enkephalin) to delta-receptors and [3H]EKC (ethylketocyclazocine) to kappa-receptors in rat spinal cord in vitro. Midazolam (1-100 mumol/l) inhibited the binding of [3H]naloxone, [3H]DAGO, [3H]DSTLE and [3H]EKC. Sodium ions (100 mmol/l) antagonized the inhibition of binding of [3H]naloxone and [3H]DSTLE by midazolam by increasing IC50 values for midazolam. However, sodium ions potentiated the inhibition of binding of [3H]DAGO by midazolam by decreasing IC50 value for midazolam and had a mixed effect on binding of [3H]EKC in the presence of midazolam. Scatchard analysis performed in the presence of sodium ions and/or midazolam confirmed the specific effects of sodium ions as well as midazolam on the Bmax and KD of mu-, delta-, and kappa-receptors. These results suggest for the first time that sodium ions play an important role in the modulation of spinal opioid receptors by benzodiazepines. Sodium ions potentiate the inhibition of DAGO binding but antagonize the inhibition of naloxone and DSTLE binding by midazolam in rat spinal cord.
咪达唑仑是一种苯二氮䓬受体激动剂，鞘内注射时，它可增强或减弱鞘内注射吗啡对大鼠产生的抗伤害感受作用。此外，咪达唑仑在体外可抑制多种阿片类配体与脊髓阿片受体的结合[Rattan等人，《麻醉与镇痛》1991年；73:124 - 131]。本研究旨在探讨在钠离子存在的情况下，咪达唑仑对μ-、δ-和κ-配体与大鼠脊髓阿片受体结合的影响，钠离子对阿片激动剂和拮抗剂的结合具有不同的调节作用。钠离子（50 - 1000 mmol/L）选择性地增加了[³H]纳洛酮的特异性结合，但降低了阿片激动剂如[³H]DAGO（酪氨酰-D-丙氨酰-甘氨酰-甲基苯丙氨酰-甘氨醇-脑啡肽）与μ受体、[³H]DSTLE（酪氨酰-D-丝氨酰-甘氨酰-苯丙氨酰-亮氨酰-苏氨酰-脑啡肽）与δ受体以及[³H]EKC（乙基酮环唑辛）与κ受体在大鼠脊髓中的结合。咪达唑仑（1 - 100 μmol/L）抑制了[³H]纳洛酮、[³H]DAGO、[³H]DSTLE和[³H]EKC的结合。钠离子（100 mmol/L）通过增加咪达唑仑的半数抑制浓度（IC50）值，拮抗了咪达唑仑对[³H]纳洛酮和[³H]DSTLE结合的抑制作用。然而，钠离子通过降低咪达唑仑的IC50值，增强了咪达唑仑对[³H]DAGO结合的抑制作用，并且在咪达唑仑存在的情况下，对[³H]EKC的结合有混合效应。在钠离子和/或咪达唑仑存在的情况下进行的Scatchard分析证实了钠离子以及咪达唑仑对μ-、δ-和κ-受体的最大结合容量（Bmax）和解离常数（KD）的特异性作用。这些结果首次表明，钠离子在苯二氮䓬类药物对脊髓阿片受体的调节中起重要作用。在大鼠脊髓中，钠离子增强了咪达唑仑对DAGO结合的抑制作用，但拮抗了咪达唑仑对纳洛酮和DSTLE结合的抑制作用。
