Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
Behav Pharmacol. 2021 Jun 1;32(4):345-350. doi: 10.1097/FBP.0000000000000614.
Benzodiazepines bind to and act on α1-3 and α5-containing GABAA receptors. Previous studies suggest that different GABAA receptor α-subtypes mediate the various behavioral effects of benzodiazepines, which raises the possibility of combining benzodiazepines with subtype-selective GABAA receptor antagonists to improve the therapeutic profiles of benzodiazepines. This study examined the GABAA receptor subtype mediation of the tolerance to midazolam-induced antinociception in rats. Midazolam (3.2 mg/kg) significantly reduced the locomotion in rats which was prevented by the selective α1-preferring GABAA receptor antagonist β-carboline-3-carboxylate-t-butyl ester (βCCt) (3.2 mg/kg). Midazolam increased the paw withdrawal threshold as tested by the von Frey filament assay in the complete Freund's adjuvant-induced inflammatory pain model in rats, and this effect was not altered by βCCt or another α1-preferring GABAA receptor antagonist 3-propoxy-β-carboline hydrochloride (3PBC). Repeated treatment with midazolam in combination with vehicle, βCCt or 3PBC (twice daily) for 7 days led to a progressive increase of the ED50 values in the midazolam- and vehicle-treated rats, but not in other rats, suggesting the development of tolerance to midazolam but not to the combination of midazolam with α1-preferring GABAA receptor antagonists. These results suggest the essential role of the α1-subtype of GABAA receptors in mediating the development of tolerance to midazolam-induced antinociceptive effects and raise the possibility of increasing therapeutic profiles of benzodiazepines by selectively blocking specific α-subtypes of GABAA receptors.
苯二氮䓬类药物与含有 α1-3 和 α5 的 GABAA 受体结合并作用于这些受体。先前的研究表明，不同的 GABAA 受体 α 亚基介导了苯二氮䓬类药物的各种行为效应，这使得将苯二氮䓬类药物与亚型选择性 GABAA 受体拮抗剂结合以改善苯二氮䓬类药物的治疗谱成为可能。本研究检查了 GABAA 受体亚型在大鼠咪达唑仑诱导的镇痛作用耐受中的介导作用。咪达唑仑（3.2mg/kg）显著减少了大鼠的运动，而这种作用被选择性的 α1 偏好 GABAA 受体拮抗剂 β-咔啉-3-羧酸叔丁酯（βCCt）（3.2mg/kg）所预防。咪达唑仑增加了弗赖氏绒毛纤维测定法测定的爪回缩阈值，在大鼠完全弗氏佐剂诱导的炎症性疼痛模型中，而βCCt 或另一种 α1 偏好 GABAA 受体拮抗剂 3-丙氧基-β-咔啉盐酸盐（3PBC）对此作用没有影响。咪达唑仑与载体、βCCt 或 3PBC（每天两次）重复联合治疗 7 天导致咪达唑仑和载体处理的大鼠中咪达唑仑的 ED50 值逐渐增加，但其他大鼠则没有，这表明咪达唑仑的耐受性发展而不是咪达唑仑与 α1 偏好 GABAA 受体拮抗剂的组合的耐受性发展。这些结果表明 GABAA 受体的 α1 亚基在介导咪达唑仑诱导的镇痛作用的耐受发展中起重要作用，并提出通过选择性阻断特定的 GABAA 受体 α 亚基来增加苯二氮䓬类药物的治疗谱的可能性。
