Visser Sandra A G, Pozarek Susanna, Martinsson Sofia, Forsberg Tomas, Ross Svante B, Gabrielsson Johan
PK/PD section, DMPK&BAC, Local Discovery Research Area CNS & Pain Control, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden.
Eur J Pharmacol. 2005 Apr 11;512(2-3):139-51. doi: 10.1016/j.ejphar.2005.02.036.
Mechanism, onset and duration of tolerance development to clomethiazole-induced hypothermia were investigated in rats using telemetry. The hypothermic effect of clomethiazole was completely abolished for 10 days after an s.c. injection of 300 micromol/kg and the effect returned to approximately 50% in 32 days. The gamma-aminobutyric acidA (GABA(A)) receptor agonist muscimol induced hypothermia at 88 micromol/kg without any (cross-) tolerance. GABA(A) receptor antagonists, bicuculline (5.4 micromol/kg) and picrotoxin (3.3 micromol/kg), did not inhibit clomethiazole-induced hypothermia nor the tolerance. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine, counteracted clomethiazole-induced hypothermia at 3 micromol/kg but not the tolerance. Tolerance to the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT)-induced hypothermia was blocked by dizocilpine and clomethiazole but not vice versa. No pharmacokinetic interaction was observed. In conclusion, long-lasting tolerance to clomethiazole-induced hypothermia does not involve GABA(A) or 5-HT(1A) receptor functions. Glutamate via NMDA receptors may be involved in the hypothermic response but not in the tolerance.
采用遥测技术在大鼠中研究了对氯美噻唑诱导的体温过低产生耐受性的机制、起效时间和持续时间。皮下注射300微摩尔/千克氯美噻唑后，其降温作用在10天内完全消失，32天时作用恢复至约50%。γ-氨基丁酸A（GABA(A)）受体激动剂蝇蕈醇在88微摩尔/千克时可诱导体温过低，且无任何（交叉）耐受性。GABA(A)受体拮抗剂荷包牡丹碱（5.4微摩尔/千克）和印防己毒素（3.3微摩尔/千克）既不抑制氯美噻唑诱导的体温过低，也不抑制耐受性。非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂地佐环平在3微摩尔/千克时可对抗氯美噻唑诱导的体温过低，但不能对抗耐受性。对5-羟色胺(1A)（5-HT(1A)）受体激动剂R-(+)-8-羟基-2-(二正丙基氨基)四氢萘（R-8-OH-DPAT）诱导的体温过低的耐受性被地佐环平和氯美噻唑阻断，但反之则不然。未观察到药代动力学相互作用。总之，对氯美噻唑诱导的体温过低的长期耐受性不涉及GABA(A)或5-HT(1A)受体功能。经由NMDA受体的谷氨酸可能参与体温过低反应，但不参与耐受性。
